Molecules 28 00774

molecules
Review
TRPV3: Structure, Diseases and Modulators
Wuyue Su † , Xue Qiao † , Wumei Wang † , Shengnan He, Ke Liang and Xuechuan Hong *
State Key Laboratory of Virology, College of Science, Research Center for Ecology,
Laboratory of Extreme Environmental Biological Resources and Adaptive Evolution,
Medical College, Tibet University, Lhasa 850000, China
* Correspondence: xhy78@whu.edu.cn
† These authors contributed equally to this work.
Abstract: Transient receptor potential vanillin 3 (TRPV3) is a member of the transient receptor
potential (TRP) superfamily. As a Ca2+ -permeable nonselective cation channel, TRPV3 can recognize
thermal stimulation (31–39 ◦ C), and it plays an important regulatory role in temperature perception,
pain transduction, skin physiology, inflammation, cancer and other diseases. TRPV3 is not only
activated by the changes in the temperature, but it also can be activated by a variety of chemical
and physical stimuli. Selective TRPV3 agonists and antagonists with regulatory effects and the
physiological functions for clinical application are highly demanded. In recent years, significant
progress has been made in the study of TRPV3, but there is still a lack of modulators with a strong
affinity and excellent selectivity. This paper reviews the functional characteristics of TRPV3 in terms
of the structure, diseases and the research on TRPV3 modulators.
Keywords: TRPV3; structure; diseases; agonists; antagonists
1. Introduction
TRP channels: Transient receptor potential (TRP) channels are a class of nonselective
cationic channel proteins that are widely distributed in the peripheral and central nervous
systems. TRPs were first identified in the mutant Drosophila melanogaster with impaired
visual transmission [1]. In 1975, Minke named TRP for the first time based on its elec-
trophysiological phenotypes [2]. The TRP superfamily plays important roles in humans,
Citation: Su, W.; Qiao, X.; Wang, W.;
Drosophila, mice and worms. The TRP superfamily proteins consist of several significant
He, S.; Liang, K.; Hong, X. TRPV3:
Structure, Diseases and Modulators.
sequence elements and domains, and the amino-(N-) and carboxy-(C-) terminus structures
Molecules 2023, 28, 774. https://
are composed of a cytoplasmic ankyrin repeat domain (ARD), a connector domain, an
doi.org10.3390/molecules28020774
S1–S4 domain, an S5–S6 pore domain, a tryptophan domain and a C-terminal domain
(Figure 1) [3,4]. The TRP channels consist of seven subfamilies: TRPM subfamily (M for
Academic Editor: Simona Collina
melastatin), TRPC subfamily (C for canonical), TRPA subfamily (A for ankyrin), TRPV
Received: 20 November 2022 subfamily (V for vanilloid), TRPP subfamily (P for polycystin), TRPML subfamily (ML
Revised: 4 January 2023 for mucolipin) and TRPN subfamily (N for nonmechanoreceptor). Although the TRP
Accepted: 8 January 2023 superfamily is defined according to its structural characteristics, the amino acid sequence
Published: 12 January 2023 identity value of all of the TRP families is ~20%, which mainly covers the transmembrane
structure. The TRP superfamily has been found to participate in sensory transduction
pathways, including light perception, temperature perception, mechanical perception and
chemical perception [5–8]. In particular, the TRP channel, on the basis of pain and tem-
Copyright: © 2023 by the authors. perature perception, has attracted a lot of attention recently [6,9,10]. In addition, the TRP
Licensee MDPI, Basel, Switzerland. superfamily is involved in many other physiological processes, including Ca2+ and Mg2+
This article is an open access article
homeostasis, stress regulation, lysosomal function, inflammation, cardiovascular regulation,
distributed under the terms and
salivary secretion and smooth muscle tone functions [11–18]. The TRP superfamily is also
conditions of the Creative Commons
closely associated with human diseases because of its involvement in many physiological
Attribution (CC BY) license (https://
processes [19].
creativecommons.org/licenses/by/
4.0/).
Molecules 2023, 28, 774. https://doi.org/10.3390/molecules28020774 https://www.mdpi.com/journal/molecules

Molecules 2023, 28, x FOR PEER REVIEW 2 of 27
Molecules 2023, 28, 774 2 of 28
Figure1.1.The
Figure Thestructural
structuraldiagram
diagramofof the
the TRP
TRP channel
channel subfamily,
subfamily,its
itsmain
mainsubunits
subunits(A)
(A)and
andtoptop(B,D)
(B,D)
and
andside
side(C,E)
(C,E)views
views of
ofthe
the3D
3Dcryo-EM
cryo-EM reconstruction
reconstruction of
of TRPV3
TRPV3 in
in the
the apo
apo (closed)
(closed) state
state [20,21].
[20,21].
Reprinted
Reprintedwith
withpermission
permissionfrom
fromRef.
Ref.[20].
[20].2015,
2015,Springer
SpringerNature.
Nature.
TRPV subfamily: The

TRPV subfamily: TheTRPVTRPVchannel
channel protein
protein isisaamember
member of ofthe
theTRP
TRPsuperfamily
superfamily
that
that was first identified in 1997 and systematically reported in 2001 [11,22]. The
was first identified in 1997 and systematically reported in 2001 [11,22]. The TRPV
TRPV
subfamily is named for the vanilloids (e.g., capsaicin) that activate
subfamily is named for the vanilloids (e.g., capsaicin) that activate the first member of this the first member of
this subfamily, TRPV1. The TRPV subfamily includes TRPV1,
subfamily, TRPV1. The TRPV subfamily includes TRPV1, TRPV2, TRPV3, TRPV4, TRPV5 TRPV2, TRPV3, TRPV4,
TRPV5
and TRPV6and TRPV6 ion channels
ion channels with different
with different functions
functions [23–26].
[23–26]. TRPV3 TRPV3 ion channels
ion channels have ahavelow
asequence
low sequence identity value compared with other TRPV ion
identity value compared with other TRPV ion channels. The sequence identity channels. The sequence
identity values of the TRPV1, TRPV2, TRPV4 and TRPV5/6 channels is ~42%, ~43%, ~41%
values of the TRPV1, TRPV2, TRPV4 and TRPV5/6 channels is ~42%, ~43%, ~41% and
and ~28%, respectively [26]. In addition, TRPV2, TRPV3, TRPV4 and TRPV5/6 share
~28%, respectively [26]. In addition, TRPV2, TRPV3, TRPV4 and TRPV5/6 share ~47%,
~47%, ~42%, ~46% and ~28% similarity with TRPV1, respectively (Figure 2) [26,27]. TRPV3
~42%, ~46% and ~28% similarity with TRPV1, respectively (Figure 2) [26,27]. TRPV3 is a
2+ -permeable
is a temperature-sensitive and Ca nonselective cation channel that forms a
temperature-sensitive and Ca2+-permeable nonselective cation channel that forms a
tetramer complex through six transmembrane domains [24]. Like other calcium channel
tetramer complex through six transmembrane domains [24]. Like other calcium channel
proteins, TRPV3 channels exert physiological functions and influence the body by con-
proteins, TRPV3 channels exert physiological functions and influence the body by
trolling the Ca2+ flow into the cells through the stimulation of extracellular signals. The
controlling the Ca2+ flow into the cells through the stimulation of extracellular signals. The
opening of these channels may lead to the increase in the intracellular calcium concentration
opening of these channels may lead to the increase in the intracellular calcium
and the membrane depolarization of the receptor cells, thereby promoting the release of
concentration and the membrane depolarization of the receptor cells, thereby promoting
action potentials and the activation of intracellular signal transduction mechanism, thus
the release of action potentials and the activation of intracellular signal transduction
regulating the physiological function of the cells. In 2018, Appu K. Singh et al. successfully
mechanism,
revealed thus regulating
the cryo-electron the physiological
microscopy structure function of themechanism
and gating cells. In 2018, Appu K.
of mouse Singh
TRPV3
et al. successfully revealed the cryo-electron microscopy structure
channels in open and closed states for the first time (Figure 1) [21]. TRPV3 is known to and gating mechanism
of mouse
have TRPV3 channels
a temperature activationinthreshold
open and of closed
31–39 ◦states
C. Thefor the firstmechanism
molecular time (Figure 1) [21].
of TRPV3
TRPV3 is known to have a temperature activation threshold
thermal activation is not fully understood. Grandl et al. screened 14,000 random mutant of 31–39 °C. The molecular
mechanism
clones and foundof TRPV3 thermal
that five aminoactivation is not
acid residues fully I644,
(N643, understood.
N647, L657 Grandl
and et al. screened
Y661) located
14,000 random mutant clones and found that five amino
in the transmembrane segment of S6 and the adjacent pore loop play an important acid residues (N643, I644, N647,
role
L657
in the and Y661)activation
thermal located inofthe transmembrane
TRPV3 [28]. Sung Eun segment
Kim of et S6
al. and
foundthethat
adjacent poreL655
I652 and loop
play an important role in the thermal activation of TRPV3 [28].
also mediated the thermal response of TRPV3 near the above sites [29]. TRPV3 can also be Sung Eun Kim et al. found
that I652 or
activated and L655 also
inhibited bymediated the thermal
certain endogenous response
ligands, of TRPV3
natural near and
products, the above sites [29].
small-molecule
TRPV3 can
synthetic also be activated
chemicals. Changesor in inhibited by certain
the extracellular endogenous
cations, ligands,voltage
pH, membrane naturaland
products,
other
and small-molecule
physiological factors can synthetic
regulate chemicals.
the functionChanges
of TRPV3.inTRPV3 the extracellular
is distributedcations,
throughout pH,
membrane voltage and other physiological factors can regulate the
various tissues, including the intestinal epithelial cells, vascular endothelial cells, epidermal function of TRPV3.
TRPV3 is distributed
keratinocytes, throughout
oral epithelial variousepithelial
cell, corneal tissues, including
cells, dorsal theroot
intestinal epithelial
ganglion cells,
and central
Molecules 2023, 28, 774 3 of 28
vascular endothelial cells, epidermal keratinocytes, oral epithelial cell, corneal epithelial
cells, dorsalsystem
nervous root ganglion
neuronsand centralInnervous
[30,31]. contrastsystem
to otherneurons [30,31]. Inincontrast
TRP channels the sameto other
family,
TRP channels in the same family, TRPV3 channels show unique sensitization
TRPV3 channels show unique sensitization rather than desensitization upon repeated rather than
desensitization upon repeated stimulation [32]. TRPV3 channels play an important
stimulation [32]. TRPV3 channels play an important role in maintaining the normal physio- role in
maintaining the normal physiological functions of the body, and they have been
logical functions of the body, and they have been found to be involved in temperature and found to
bepain
involved in temperature
perception. In addition,and pain channels
TRPV3 perception.alsoInplay
addition, TRPV3 role
an important channels
in thealso play
generation
anofimportant role in
skin and hair. the generation
TRPV3-null mice of skin impaired
exhibit and hair. skinTRPV3-null
function,mice exhibithair
including impaired
growth,
skin
skinfunction, includingwound
barrier formation, hair growth,
healing,skin
skinbarrier
pain and formation, wound[24,26,33–36].
itch production healing, skinFinding
pain
and itch production [24,26,33–36]. Finding and screening TRPV3 modulators
and screening TRPV3 modulators with high activity and selectivity may provide a new with high
activity
way ofand selectivity
treating may
related provide a new way of treating related diseases.
diseases.
Figure 2. The similarity between TRPV1-6.

Figure 2. The similarity between TRPV1-6.
2. Diseases Related to TRPV3
2. Diseases Related to TRPV3
Since TRPV3 plays an indispensable role in the generation of pain, the research on
SinceinTRPV3
TRPV3 plays anmainly
early studies indispensable
focused role in the
on pain generation
sensation andofthermal
pain, the research With
sensation. on
TRPV3
furtherinstudies
early studies mainly focused
on physiological on having
functions pain sensation and thermal
been conducted, TRPV3 sensation.
has beenWith
found
further studies on with
to be associated physiological
a variety functions having
of diseases (Tablebeen
1). conducted, TRPV3 has been found
to be associated with a variety of diseases (Table 1).
Table 1. TRPV3 and diseases.
Table 1. TRPV3 and diseases.
Diseases Research Evidence Reference(s)
Olmsted A series of independent clinical reports are identified mutations in the TRPV3 gene as
Olmsted A series of independent clinical reports are identified mutations in the TRPV3 [37–42]
syndrome (OS) the cause of Olmsted’s syndrome. [37–42]
syndrome (OS) gene as the cause of Olmsted’s syndrome.
1. The expression of TRPV3 is significantly increased in skin lesions and non-diseased
1. The expression of TRPV3 is significantly increased in skin lesions and non-
skin of patients with specific dermatitis. 2. The pharmacological activation of TRPV3
Pruritic
Pruritic andand diseased
leadsskin
to theofdevelopment
patients with specific
of AD dermatitis.
in wild-type mice,2.and
The pharmacological
it has no effect on TRPV3 [43–45]
atopic dermatitis (AD)
atopic dermatitis activation of TRPV3
knockout mice. 3. leads to the development
The inhibition of TRPV3 treatsof inflammatory
AD in wild-type mice,
dorsal skin and
in a it has [43–45]
(AD) dose-dependent
no effect on TRPV3 manner.
knockout mice. 3. The inhibition of TRPV3 treats
inflammatory dorsallevel
1. The expression skinof
inTRPV3
a dose-dependent manner.
in psoriasis patients is significantly higher than it is in
Psoriasis 1. Thepeople withoutlevel
expression psoriasis. 2. TRPV3
of TRPV3 antagonists
in psoriasis relieve is
patients thesignificantly
symptoms inhigher
patientsthan
withit [46]
moderate-to-severe psoriasis in a dose-dependent manner.
Psoriasis is in people without psoriasis. 2. TRPV3 antagonists relieve the symptoms in [46]
1. TRPV3
patients with knockout mice show nopsoriasis
moderate-to-severe increase in
inscratching behavior after
a dose-dependent itch modeling. 2.
manner.
Cutaneous
The expression of TRPV3 is significantly up-regulated in the epidermis of patients with [47,48]
pruritus
pruritus after having been burnt.
Molecules 2023, 28, 774 4 of 28
Table 1. Cont.

Rosacea TRPV3 gene expression is significantly increased in rosacea. [49]
1. TRPV3 expression is increased in pancreatic, bone, breast, lung and oral squamous
Cancer [21,50–52]
cell cancers. 2. TRPV3 expression is decreased in colorectal cancer.
1. The expression of TRPV3 is increased in pathological cardiac hypertrophy. 2. TRPV3
Myocardial expression is increased in cardiomyocyte hypertrophy induced by Ang-II in vitro. 3.
[53]
hypertrophy TRPV3 inhibitors can significantly aggravate cardiomyocyte hypertrophy and TRPV3
antagonists can slow cardiomyocyte hypertrophy.
TRPV3 activation exacerbate cardiac dysfunction and interstitial fibrosis in
Cardiac fibrosis [54]
pressure-overloaded rats.
Myocardial The expression of TRPV3 is significantly up-regulated in neonatal rat cardiomyocytes
[55]
infarction after myocardial infarction and in hypoxia-treated rats.
TRPV3 is overexpressed in skin pain, breast pain, cancer pain and other
Pain [56–58]
pain-experiencing tissues.
TRPV3 agonists inhibit hair growth, whereas TRPV3 inhibitors significantly reverse the
Alopecia [59]
symptom.
2.1. Skin Diseases

The TRPV3 channel is essential for skin barrier formation, keratinocyte maturation,
wound healing and itching. The overexpression of TRPV3 can lead to hair loss, skin inflam-
mation, severe pruritus and dermatitis [42]. Olmsted syndrome (OS), also known as dermal
keratosis and perioral dermatosis, is a rare keratosis with autosomal dominant inheritance.
Exon sequencing has revealed that an autosomal dominant heterozygous missense mu-
tation encoding TRPV3 causes OS. It is characterized by bilateral palmoplantar keratosis
(PPK) and peripheral keratosis plaques, and all of them cause severe pruritus [41,60]. Stud-
ies applying the patch-clamp analysis technique to TRPV3-expressing mutants have shown
that these mutations lead to greater inward currents, resulting in elevated intracellular
Ca2+ and induced increased apoptosis in the epidermal cells, suggesting that increased cell
death may drive OS [61]. The clinical treatment of OS is usually administered with antide-
pressants, opioids, anticonvulsants and nonsteroidal anti-inflammatory drugs. The topical
treatments include antidotes, retinoic acid and corticosteroids. The systemic treatments
includes the use of norepinephrine or retinoic acid. Surgical treatments are performed
on regular scabs using skin grafts [60]. It was reported that the EGFR inhibitor, Erlotinib,
has been reported clinically for the treatment of OS [60]. However, these treatments are
ineffective and prone to relapse. OS is a disease that is caused by the TRPV3 gene muta-
tion, and TRPV3 gene knockout mice have demonstrated significant pruritus inhibitory
behavior [41]. A large number of studies have shown that the topical application of TRPV3
inhibitors can effectively inhibit skin pruritus and pain, which provides a new idea for
the treatment of intractable pruritus and pain diseases such as Olmsted syndrome and
hereditary palmoplantar keratosis.
In addition to hereditary Olmsted syndrome pruritus, TRPV3 is closely associated
with the development and progression of various skin diseases since it is significantly
increased in the epidermal cells of patients with acquired skin diseases such as rosacea,
psoriasis and atopic dermatitis. Studies on the skin tissues of burn patients showed that
the expression of TRPV3 was significantly upregulated in the epidermis of patients with
post-burn pruritus [48]. The activation of TRPV3 ion channels in keratinocytes resulted in
the release of histamine, TSLP, chemokines and cytokines, which further stimulated the
sensory input of adjacent skins by acting as intercellular messengers, thereby inducing skin
pain and itching (Figure 3). The inhibition of the TRPV3 channels is a new idea for the
treatment of skin diseases, and many scientists have begun to focus on the discovery of
TRPV3 inhibitors [62–65].
Molecules 2023, 28, 774 5 of 28

the treatment of skin diseases, and many scientists have begun to focus on the discovery
of TRPV3 inhibitors [62–65].
Figure 3.
Figure 3.The
Therole
roleofof
TRPV3 in itch
TRPV3 signal
in itch and and
signal cell proliferation. ERK, extracellular
cell proliferation. signal-regulated
ERK, extracellular signal-regulated
kinase; ADAM17, metalloprotease ADAM17; DAG, diacylglycerol; IP3, inositol trisphosphate; PIP2,
kinase; ADAM17, metalloprotease ADAM17; DAG, diacylglycerol; IP3, inositol trisphosphate; PIP2,
phosphatidylinositol(4,5)bisphosphate; PLC, phospholipase C; CNS, central nervous system; TSLP,
phosphatidylinositol(4,5)bisphosphate;
thymic stromal lymphopoietin [34]. PLC, phospholipase C; CNS, central nervous system; TSLP,
thymic stromal lymphopoietin [34].
2.2. Cancers
2.2. Cancers
It has been reported that the high expression of TRPV3 will cause pain in pancreatic
It has
cancer, bonebeen reported
cancer thatcancer
and breast the high[21].expression of TRPV3
Patients often willpain
experience cause painbreast
before in pancreatic
cancer, bone cancer
cancer surgery, and breast
and there cancer
is evidence that[21].
thisPatients often
pain is due experience
to the pain before
high expression breast cancer
of TRPV3
surgery,
[56,66–68].and thereHoeft
Birgit is evidence that this392
et al. analyzed pain is due
single to the high
nucleotide expression of
polymorphisms ofTRPV3
43 genes [56,66–68].
associated
Birgit Hoeft with fatty
et al. acid metabolism
analyzed 392 single and the risk of polymorphisms
nucleotide colorectal cancer in ofa43study
genes involving
associated with
1225 acid
fatty cancer patients and
metabolism 2032
and thenoncancer controls.cancer
risk of colorectal TRPV3inwas also shown
a study involvingto be1225
associated
cancer patients
with a higher risk of colorectal cancer [69]. Mehmet Emin Kalender
and 2032 noncancer controls. TRPV3 was also shown to be associated with a higher et al. analyzed the risk of
tissues of 37 females and 56 males with colorectal cancer and found
colorectal cancer [69]. Mehmet Emin Kalender et al. analyzed the tissues of 37 females and that the mRNA
expression level of the TRPV3 gene was much lower than it was in the healthy tissues (p
56 males with colorectal cancer and found that the mRNA expression level of the TRPV3 gene
< 0.05) [52]. Xiaolei Li et al. also found that TRPV3 was highly expressed in 65 out of 96
was much lower than it was in the healthy tissues (p < 0.05) [52]. Xiaolei Li et al. also found
cases of lung cancer (67.7%). In general, TRPV3 expression varies across different cancers.
that TRPV3 TRPV3
Statistically, was highly expressed
expression in 65 out
is decreased in of 96 casescancer,
colorectal of lung and cancer (67.7%). in
it is increased In general,
TRPV3
pancreatic cancer, bone cancer, breast cancer, lung cancer and oral squamous celldecreased
expression varies across different cancers. Statistically, TRPV3 expression is
in colorectal[21,50,52,70].
carcinoma cancer, and it is increased
Studies have in pancreatic
shown cancer, bone
that TRPV3 may cancer,
increasebreastthe Cacancer,
2+ lung
cancer and oral
concentration in squamous
cancer cells,cell carcinoma
activate [21,50,52,70].
calmodulin Studies
kinase, and then,have
it may shown
affectthat TRPV3 may
the cell
increase
cycle andthe Ca2+ concentration
promote cell proliferation in[71].
cancer cells, activate
Importantly, calmodulin
the inhibition kinase,
of TRPV3 and then,
slowed the it may
proliferation
affect the cellofcycle
lungand
cancer cells [50].
promote cellInproliferation
conclusion, inhibiting the expression
[71]. Importantly, of TRPV 3of TRPV3
the inhibition
providesthe
slowed a new strategy for
proliferation ofthe
lungtreatment
cancer of cancer.
cells [50]. In conclusion, inhibiting the expression of
TRPV 3 provides a new strategy for the treatment of cancer.
2.3. Cardiac Diseases
2.3. Cardiac
Studies Diseases
have identified TRPV3 as a key regulator of cardiac diseases. Hongli Sun et
al. revealed
Studiesthe roleidentified
have of TRPV3 TRPV3
in the course of cardiac
as a key hypertrophy
regulator cases.
of cardiac TRPV3 was
diseases. Hongli Sun
elevated in pathological cardiac hypertrophy, and TRPV3 expression was also increased
et al. revealed the role of TRPV3 in the course of cardiac hypertrophy cases. TRPV3 was
in Ang II-induced cardiomyocyte hypertrophy in vitro. Meanwhile, the cellular
elevated in pathological cardiac hypertrophy, and TRPV3 expression was also increased in
experiments have shown that the non-selective TRPV3 inhibitor, carvacrol, can
Ang II-induced
significantly cardiomyocyte
aggravate hypertrophy
cardiomyocyte in vitro.
hypertrophy, Meanwhile,
while the cellular
the non-selective experiments
TRPV3
have shown that the non-selective TRPV3 inhibitor, carvacrol, can significantly
antagonist, ruthenium red, can slow down cardiomyocyte hypertrophy. Further studies aggravate
cardiomyocyte hypertrophy, while the non-selective TRPV3 antagonist, ruthenium red, can
slow down cardiomyocyte hypertrophy. Further studies have showed that TRPV3 activation
aggravated pathological cardiac hypertrophy through calcineurin/NFATc3 signaling [53]. In
addition, the inhibition of TRPV3 can reduce the amount of intracellular calcium ions and
further decrease cardiac autophagy activity, thereby reducing cardiomyocyte hypertrophy [72].
A series of results have suggested that TRPV3 may be a potential therapeutic target for
myocardial hypertrophy. Hongli Sun et al. further found that TRPV3 activation promoted the
proliferation of cardiac fibroblasts through the β-CDK1/CDK2/Cyclin E pathway, thereby
Molecules 2023, 28, 774 6 of 28
aggravating cardiac fibrosis [54]. Hypoxia-induced apoptosis and inflammation are important
causes of cardiovascular diseases such as myocardial infarction (MI), and TRPV3 siRNA can
protect the cardiomyocytes from hypoxia-induced apoptosis and inflammation [55]. The
current results fully demonstrated that TRPV3 may play a certain role in the occurrence and
development of cardiovascular diseases. Further elucidation of the related mechanisms will
provide new intervention targets for the prevention and treatment of cardiovascular diseases.
There are no TRPV3 antagonists in the current clinical trials, but there is evidence that TRPV3
may be a new direction for the treatment of cardiac diseases.
2.4. Others
TRPV3 is also expressed in human and mouse corneal epithelial cells, and it plays an
important role [31]. Ocular lesions including corneal dystrophy, corneal epithelial dysplasia
and lacrimal gland inflammation are common in OS patients with TRPV3 mutations [73].
It has been reported that human corneal epithelial cells (HCEC) can activate heat-sensitive
TRPV3, and TRPV3 activation can protect the cornea against harmful increases in the
ambient temperature [74]. Wound healing assays have showed that activation of TRPV3
in corneal epithelial cells accelerated the proliferation of corneal epithelial cells [31]. Inter-
estingly, the activation of TRPV3 in oral epithelial cells by heat induction can accelerate
the proliferation of oral epithelial cells and wound healing [75]. Exploring its mechanism
showed that TRPV3 and EGFR formed a signaling complex, and TRPV3 activation could
enhance the activity of EGFR signaling, and then, regulate epithelial cell proliferation [76].
A positive feedback loop was formed between TRPV3 and TGF-α/EGFR, possibly leading
to terminal differentiation of the basal keratinocytes (Figure 3). This may also explain why
the overexpression of TRPV3 has been detected in many cancer cells.
In addition, TRPV3 is closely related to pain. The overexpression of TRPV3 has been
found in skin pain, breast pain, cancer pain and other pain tissues [56–58]. The relevant
evidence has shown that the TRPV3 channels in the epidermis are involved in sensory
conduction, but the TRPV3 channels in the skin keratinocytes do not form synapses with
the sensory nerve terminals. It was speculated that small molecules may form a “bridge”
between the epidermal cells and sensory nerve terminals to complete signal transmission.
When the body is injured by the outside world, the injured tissue site will promote the
release of prostaglandin E2 (PGE2), ATP, NO, interleukin 1α (Il-1α), TGF-β and other
substances, which sensitize the sensory nerve endings of the skin [36,58]. Complete signal
transmission results in specific physiological effects.
The TRPV3 agonist, carvacrol, inhibits hair growth, and another TRPV3 inhibitor,
forsythoside B, significantly reverses it [59]. TRPV3 signaling plays an important role in
the control of human hair growth, which may be a promising target for the development of
drugs for hair growth disorders [77].
3. Small-Molecule TRPV3 Modulators

In recent years, a number of small-molecule modulators including natural and syn-
thetic compounds were identified to show specific effects on various functions through
acting at the TRPV3 channels in academic and pharmaceutical industry laboratories.
3.1. TRPV3 Agonists

3.1.1. Natural Compounds
Camphor (Table 2, entry 3) is one of the early natural compounds that was identified to
activate TRPV1, TRPV3, TRPM8 and TRPA1 channels [78,79]. The activation of TRPV1 and
TRPV3 channels could enhance thermal sensitivity, and the activation of TRPM8 could in-
duce cold sensitivity [80]. In addition, the TRPV3 channels in the brain may also play a role
in mood regulation. Incensole acetate (IA) (Table 2, entry 1), isolated from Boswellia resin,
was an effective TRPV3 agonist to induce anti-anxiety and anti-depressive behavior effects
in wild-type (WT) mice with an EC50 of 16 µM [81]. Additional research has suggested that
incensol may be a good candidate for neuroprotection because of its multipotent active
Molecules 2023, 28, 774 7 of 28
mechanisms, including modulating TRPV3 and the pro-inflammatory transcription factor

STAT3 [82]. Serratol (Table 2, entry 2), an analog of IA isolated from Indian frankincense,
showed more TRPV3 inhibitory activity, with an IC50 of 0.15 ± 0.01 µM [82]. Haoxing Xu
et al., using Ca2+ imaging and patch-clamp recordings, demonstrated that carvacrol (Table 2
entry 6), thymol (Table 2, entry 10) and eugenol (Table 2, entry 7) can activate the TRPV3
channels that are allogenically expressed in HEK293 cells and the endogenous TRPV3 chan-
nels in epithelial cells and keratinocytes [63]. In addition, carvacrol can activate TRPA1,
and Eugenol can activate TRPV1 [63,83]. A recent study reported that carvonol interacts
with L508, a key residue in the S2–S3 linker, leading to conformational change in or the
conformational rearrangement and opening of the TRPV3 channels [84]. Citral, a bioactive
component of lemongrass, can activate the TRPV1, TRPV3, TRPM8 and TRPA1 channels. It
has a long-term inhibitory effect on TRPV1-3 and TRPM8 channels, and it can temporar-
ily block the TRPV4 and TRPA1 channels. The broad spectrum and long-term sensory
inhibitory activity of citral may be more effective than that of capsaicin in the treatment of
abnormal pain, pruritus or other types of pain involving the superficial sensory nerves and
skin [85]. AK Vogt-Eisele et al. found more than 30 compounds with excitatory effects on
TRPV3 by screening the natural chemical library of monoterpenoids. Six compounds with a
ring-located hydroxyl group have better TRPV3 activity than camphor does (Table 2, entries
3–4, 6, 9–12) [86]. A structure–activity relationship study discovered that the secondary
hydroxyl group was the structural requirement for the effective activation of TRPV3. The
oxidation of the secondary hydroxyl to the carbonyl group will significantly reduce the
activity of the substance. In addition, Hanns Hatt et al. found that monoterpenoids can
strongly activate the TRPV3 channels, and this can result in differential desensitization. The
desensitization of TRPV3-mediated currents is agonist specific and time dependent [87]. It
was reported that most single-thread compounds, such as camphor, borneol and menthol,
mainly activate the hot channel TRPV3 at mild temperatures, while at low temperatures,
they mainly activate the cold channel TRPM8. This explains why applying peppermint to
the skin burns and tingles at high temperatures, and it cools at low temperatures [88–91].
Cannabinoids and their derivatives (Table 2, entries 13, 14) stimulate the TRPV3-mediated
Ca2+ influx. Cannabidiol (CBD) and tetrahydrocannabinoids have higher potency and
efficacy, with EC50 values of 3.8 ± 0.4 µM and 3.7 ± 1.6 µM, respectively [92]. CBD can
activate a variety of TRP channels, including TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and
TRPA1. Studies have shown their pharmacological effects on inflammation, pain, cancer,
acne, drug dependence, seizure anxiety and Parkinson’s and Alzheimer’s diseases [93,94].
3.1.2. Synthetic Compounds

The first known synthetic small-molecule activator of TRPV3 is 2-Aminoethoxydiphenyl
borate (2-APB) (Table 2, entry 15) [95,96]. Hu and colleagues found that the activation
mechanism of 2-APB in TRPV3 is distinct from the others. It relied on two essential
cytoplasmic residues (His426 and Arg696), which are required for TRPV3 sensitivity to
2-APB, but not to camphor or voltage [95]. Unfortunately, 2-APB is not a specific agonist for
TRPV3. In addition to inhibiting IP3-induced Ca2+ release and most of the TRP channels,
2-APB can activate TRPV1, TRPV2 and TRPV3 at high concentrations [97–99]. Compounds
with similar structures to 2-APB, such as diphenylboinic anhydride (DPBA) and drofenine,
are also effective TRPV3 agonists (Table 2, entries 16, 17) [100].
3.1.3. Endogenous Substances

Farnesic pyrophosphate (FPP) is a key substance in the isoprene pathway, and it is also
the precursor of numerous terpenoids, and it is widely used in combinatorial biology. FPP
can be biosynthesized by a series of enzymatic reactions, with acetyl-CoA being used as the
initial starting material (Table 2, entry 18). FPP is a specific TRPV3 activator with an EC50
value of 0.13 µM [35]. FPP can induce intracellular calcium channel reactions and activate
membrane currents in HEK293 cells and primary keratinocytes transfected with human
TRPV3. The injection of FPP into mouse paws can induce thermal hypersensitivity reactions
Molecules 2023, 28, 774 8 of 28
and acute injurious behavior. The symptom can be reduced when TRPV3 is knocked down
by TRPV3 shRNA [35]. Interestingly, vitamin B3, which is also known as nicotinic acid
(NA), can enhance TRPV3 activity while inhibiting TRPV2 and TRPV4 [101]. In addition,
NO, a pleiotropic cellular signaling molecule that controls a variety of biological processes,
can activate TRPV3 through cysteine nitrosation (Table 2, entry 19) [102]. Inflammatory
conditions can further enhance the activity of the TRPV3 channels. The downstream
elements of the inflammatory cascade reaction and endogenous ligands such as arachidonic
acid and protein kinase C (PKC) can sensitize/activate the TRPV3 channels [103].
3.2. TRPV3 Antagonists

3.2.1. Natural Compounds
Recently, Yalan Han et al. identified citrusinine II, an acridone alkaloid isolated from
the medicinal plant Atalantia monophylla (L.) DC (Table 3, entry 1). It directly interacts with
Y564 within the S4 helix of TRPV3 and selectively inhibits the TRPV3 channel with an
IC50 of 12.43 µM [104]. Studies had shown that subcutaneous injection of citrusinine II
(143 ng/skin part) almost completely inhibited itching behaviors, and it had an obvious
analgesic effect [104]. Coumarin osthole is the main bioactive component of the natural
Cnidium monnieri plant, and it is commonly used in traditional Chinese herbal treatments,
including anti-itching and anti-dermatitis treatments. Xiaoying Sun et al. showed that
osthole was a specific inhibitor of the TRPV3 channel, which can effectively inhibit the
itching sensation, with an IC50 of 37.0 ± 1.9 µM (Table 3, entry 2) [105]. Recently, Arthur
Neuberger et al. further elucidated the binding site and inhibition mechanism of coumarin
osthole and TRPV3 by applying cryogenic electron microscopy [106]. Studies have shown
that TRPV3 has two binding sites for coumarin osthole in the transmembrane region. One
of them is located in a pocket structure formed by the intracellular half of the S1–S4 bundle
and the C-terminal portion of the TRP helix, and the other one is located in nexus of the
linker domain and pre-S1 region [106]. Coumarin osthole induced the closure of TRPV3
ion channels by binding to these two binding sites and converted the TRPV3 ion channel
pore into a previously unknown conformation [106]. Interestingly, these two binding sites
coincide with the agonist 2-APB binding site [106]. Hang Qi et al. studied the active
components of the herb Achillea alpine, isochlorogenic acid A (IAA) and isochlorogenic acid
B (IAB) (Table 3, entries 3,4), which can reduce ear swelling, keratinocyte death and chronic
itching caused by over-activated TRPV3 [107]. They are selective inhibitors of TRPV3, and
the TRPV3 channel opening probabilities decreased from 26.9 ± 5.5% to 3.7 ± 1.2% and
3.2 ± 1.1%, respectively. The IC50 values were 2.7 ± 1.3 µM for IAA and 0.9 ± 0.3 µM for
IAB. Kewei Wang et al. identified natural forsythoside B as a new selective inhibitor of
TRPV3 from Lamiophlomis rotata, which can alleviate acute and chronic itching by inhibiting
the TRPV3 channel function, with an IC50 value of 6.7 ± 0.7 µM (Table 3, entry 5) [108].
Verbascoside, a phenylethanoid, specifically inhibited the TRPV3 channel, with an IC50 of
14.1 ± 3.3 µM (Table 3, entry 7) [109]. Marine sponges contain many small-molecule natural
products. Among them, guanidine alkaloids have unique structures and diverse biological
activities. Of these, the acyclic guanidine alkaloids, pulchranin A, B and C, had inhibitory
effects on TRPV3, with the EC50 values of 71.8 ± 9.4 µM, 117.9 ± 11.8 µM and >200 µM,
respectively (Table 3, entries 8–10) [110,111]. In 2013, Yuliya Korolkova et al. isolated the
cycloguanidine alkaloids, monanchomycalin B and urpocidin A, from marine sponges, and
they are the antagonists of the TRPV1, TRPV2 and TRPV3 channels. Monanchomycalin
B had very good activity, with EC50 values of 6.02 µM, 2.84 µM and 3.25 µM for TRPV1,
TRPV2 and TRPV3, respectively (Table 3, entry 6) [112].
3.2.2. Synthetic Compounds

Ruthenium red (Table 3, entry 11), a water soluble polycationic dye, is an inhibitor
of the TRPV family and TRPA1 and the most common TRPV3 channel inhibitor [113,114].
Interestingly, 2,2-diphenyltetrahydro-furan (DPTHF), an analogue of 2-APB, is also an
inhibitor of TRPV3 channels (Table 3, entry 12) [115]. Fang Zhang et al. found the lead
Molecules 2023, 28, 774 9 of 28
compound, 2,6-dimethoxy-n-(4-(trifluoromethyl)phenyl)oxazol-2-ylbenzamide, by per-

forming structure-based virtual screening and further optimized the structure to obtain
the more active TRPV3 antagonist N-(5-chloro-4-(4-(trifluoromethyl) pheny l) oxazol-2-yl)-
2,6-dimethoxybenzamide (PC5), with an IC50 of 2.63 ± 0.28 µM (Table 3, entry 13) [116].
Mengqi Lv et al. analyzed the structure of forsythoside B and proposed that cinnamate
ester is the key fragment. A total of 23 targeted compounds were synthesized through
a series of chemical modifications. Compound 7C showed the highest TRPV3 inhibitory
efficiency, with an IC50 value of 1.05 µM, and it showed good selectivity against TRPV1
and TRPV4 channels (Table 3, entry 14) [117].
Local anesthetics play an important role in the treatment of clinical pruritus and the
inhibition of various types of pain. To further explore the potential mechanism of the
analgesic effect of local anesthetics, it is necessary to investigate the interaction between
local anesthetics and TRP ion channels. Recently, Reiko Horishita et al. discovered the
interaction between local anesthetics and TRPV3 channels. The results show that the
charged form of the local anesthetic interacts with the TRPV3 ion channel outside the cell.
The degree of inhibition is positively correlated with the concentration of local anesthetic.
The IC50 values of bupivacaine, mepivacaine, lidocaine and ropivacaine were 0.69 ± 0.41,
1.4 ± 0.3, 0.28 ± 0.04, 2.5 ± 0.5 and 0.17 ± 0.04 mM, respectively (Table 3, entries 15–18) [118].
Qiang Liu et al. reported that the local anesthetic dyclonine also had TRPV3 inhibitory
activity, with an IC50 of 3.2 µM (Table 3, entry 19) [119]. A series of studies suggest that the
inhibition degree of local anesthetics on TRPV3 ion channels is positively correlated with
the concentration. To better understand the molecular mechanism, Arthur Neuberger et al.
used cryo-EM to characterize the protein structure of the TRPV3–dyclonine complex [120].
Dyclonine binds to the central void of the ion channels to block the passage of extracellular
Ca2+ , and then, it inhibits the activity of TRPV3 [120]. These findings help us to further
explore the mechanisms of local anesthetics, which may be used to treat various diseases
caused by TRPV3 agitation.
Hydra Biosciences Inc., Glenmark and Abbvie Inc. have shown intensive interest in
the small-molecule inhibitors of TRPV3 channels. Hydra Biosciences reported on a series of
tetrahydroquinoline amide TRPV3 inhibitors [121]. Example #64 had an IC50 of 0.2–1 µM,
and it was highly selective (>40-fold vs. other TRP channels), reducing the heat sensitivity
after a carrageenan injection in burned areas or the hind paws (Table 3, entry 20). In addi-
tion, the quinazolinone compound, DCP-THQ, showed almost no activity against TRPV1,
TRPV4, TRPM8 and TRPA1, with an IC50 of 117 nM for TRPV3 (Table 3, entry 21) [122,123].
The Glenmark Pharmaceutical Company described additional quinazolinone analogs, which
are similar to the chemical structure previously disclosed by Hydra (Table 3, entry 22) [124].
The Glenmark Pharmaceutical Company further extended the intellectual property rights
by describing TRPV3 antagonists of the thiophene [125], chromioylamide [126], chromioke-
tone [127], imidazole [128] and benzimidazole [129] classes (Table 3, entries 23–28). Abbvie
reported on the synthesis and biological characteristics of a series of (pyridine-2-yl) methanol
derivatives. The dominant molecule, cis-3-[(S)-hydroxy(pyridin-2-yl)methyl]-1-methyl-3-[4-
(trifluoromethyl)pyrid-in-2-yl]cyclobutanol (74a), had strong TRPV3 inhibitory activity, with an
IC50 of 0.38 µM, which was effective in a rat neuropathic pain model (Table 3, entry 29) [130].
3.2.3. Endogenous Substances

Many natural TRPV3 modulators have been reported, but a few endogenous TRPV3
inhibitors have been discovered. A few endogenous lipid metabolites have TRPV3 inhibitory
activities. A member of the docosahexaenoic acid-derived lipidolytic family, 17 (R)-resolvin
D1 (17R-RVD1), was reported to be a specific TRPV3 inhibitor, with an IC50 of 0.4 µM, which
significantly reduced the level of TRPV3-mediated abnormal pain (Table 3, entry 30) [131].
Interestingly, endogenous TRPV3 agonists, such as the precursor molecule isopentenyl py-
rophosphate (IPP), are endogenous TRPV3 antagonists synthesized by the mevalonate pathway
(Table 3, entry 31). The IC50 values were 0.24 µM and 7.5 µM, respectively, and they performed
extensive analgesic actions [132].
Molecules
Molecules 2023, 28, 7742023, 28, x FOR PEER REVIEW 10 of 28 11 of 2
Table 2. TRPV3 agonists.

Entry Name Table 2. TRPV3 agonists.
Structure Activate Inhibit EC for TRPV3 Description/Use Reference(s)
Structure Activate Inhibit 50
EC50 for TRPV3 Description/Use Reference(s)
Structure Activate Inhibit EC50 for TRPV3 Description/Use Reference(s)
Entry compounds
Natural compounds
Natural Name Structure Activate Inhibit EC50 for TRPV3 Description/Use Reference(s)
Entry compounds
Entry compounds
Natural compounds
Natural compounds
A Boswellia
A Boswellia resin component resincan
component
induce anti-anxiety-like
Incensole
Incensole A Boswellia resin
cancomponent can induce anti-anxiety-like
induce anti-anxiety-like
1 1 Incensole TRPV3
TRPV3 — — 16 μM A Boswellia
and
16 µM resin
antidepressantcomponent
behavior can induce
effects anti-anxiety-like
in wild-type (WT)
[81] [81]
1 Incensole
acetate(IA)
acetate (IA) TRPV3 — 16 μM A Boswellia
and resin
andcomponent
antidepressant behavior can induce
effects
antidepressant anti-anxiety-like
in wild-type
behavior (WT) [81]
1 Incensole
acetate (IA) TRPV3 — 16 μM A Boswellia resin component can induce anti-anxiety-like
and antidepressant behavior effects in wild-type (WT)
mice. [81]
1 Incensole
acetate (IA) TRPV3 — 16 μM and antidepressant
mice. effectsbehavior effects
in wild-type (WT)inmice.
wild-type (WT) [81]
1 acetate (IA) TRPV3 — 16 μM and
mice.antidepressant behavior effects in wild-type (WT) [81]
acetate (IA) mice.
mice.
A TRPV3 agonist, isolated

A TRPV3 agonist, isolated
fromisolated from Indian frankincense, had
Indian frankincense,
A TRPV3 agonist, from Indianhad frankincense, had
A TRPV3
low agonist,
retrofitting isolated
potential.
low from
Its
retrofitting Indian
affinity
potential.canfrankincense,
Its had
be significantly
2 Serratol TRPV3 — 0.15 ± 0.01 μM lowA TRPV3 agonist,
retrofitting isolated
potential. from
Its Indian
affinity canfrankincense, had
be significantly [82]
2 2 Serratol
Serratol TRPV3
TRPV3 — —0.15 ± 0.01 μM A
0.15 ± TRPV3
low
0.01
improved agonist,
retrofitting
µM by the isolated
potential.
affinity can be
acylation, from
Its Indian
affinity can
significantly
esterificationfrankincense,
be had
significantly
[82]of
and oxidation [82]
2 Serratol TRPV3 — 0.15 ± 0.01 μM low retrofitting potential. Itsesterification
affinity can be
andsignificantly [82]
2 Serratol TRPV3 — 0.15 ± 0.01 μM improved
low
improved
serratol.
by the
retrofitting
by
acylation,
potential.
improved
the byIts
acylation, the affinity can be
acylation,
esterification and
oxidation of
significantly
oxidation of [82]
2 Serratol TRPV3 — 0.15 ± 0.01 μM serratol.
improved by the acylation,and esterification [82]
improved
serratol. by the esterification oxidation ofand
acylation, esterification
oxidation of
and oxidation of
serratol. serratol.
serratol.
TRPV1
TRPV1 Topical analgesia by desensitizing
Topical analgesia by TRPV1;TRPV1; modulated the [78,80,86,131,1
3 Camphor TRPV1
TRPV3 TRPA1 6.03 ± 1.47 mM Topical analgesia by desensitizing modulated the [78,80,86,131,1
3 Camphor TRPV1
TRPV3
TRPV1 TRPV3 TRPA1 6.03 ± 1.47 mM Topical
sensationsanalgesia
of by desensitizing
desensitizing
warmth in TRPV1;
humans. TRPV1; modulated the [78,80,86,131,132]
3 3 Camphor
Camphor TRPV1
TRPV3 TRPA1 6.03
TRPA1 ± 1.47 mM
6.03 Topical
± 1.47 mM analgesia by desensitizing TRPV1; modulated the [78,80,86,131,1
[78,80,86,131,132]
3 Camphor TRPM8
TRPV3
TRPM8
TRPM8 TRPA1 6.03 ± 1.47 mM sensations
Topical
sensations
of warmth
analgesia
of modulated
warmth
in humans.
by desensitizing
in the sensations
humans. TRPV1;
of modulated 32]
the [78,80,86,131,1
32]
3 Camphor TRPV3
TRPM8 TRPA1 6.03 ± 1.47 mM sensations of warmth in humans. 32]
TRPM8 warmth in humans.
sensations of warmth humans. 32]
TRPM8 Borneol, a common Chinese medicine, had significant
TRPV3 Borneol, a common Chinese
Borneol, a commonmedicine,
Chinesehad significant
4 (+)-Borneol TRPV3 TRPA1 3.45 ± 0.13 mM Borneol, aand
analgesic common Chinese
anti-inflammatory medicine, had
effectshad significant
by activating [86,133,134]
4 (+)-Borneol TRPV3
TRPM8 TRPA1 3.45 ± 0.13 mM Borneol,
analgesic a common
and Chinese
anti-inflammatory
medicine, had medicine,
effects
significant by significant
activating [86,133,134]
4 (+)-Borneol TRPV3
TRPM8 TRPA1 3.45 ± 0.13 mM Borneol,
analgesic
TRPM8. a common
and Chinese
anti-inflammatory medicine,
effectshad
by significant
activating [86,133,134]
4 4 (+)-Borneol
(+)-Borneol TRPV3
TRPV3 TRPM8 TRPA1TRPA1
TRPM8 3.45 ± 0.13 mM analgesic
3.45 ± 0.13 mM and anti-inflammatory
analgesic and effects by activating
[86,133,134] [86,133,134]
4 (+)-Borneol TRPM8 TRPA1 3.45 ± 0.13 mM TRPM8.
analgesic
TRPM8. and anti-inflammatory effects by activating [86,133,134]
TRPM8 TRPM8. anti-inflammatory effects by
TRPV3 TRPM8. activating TRPM8.
TRPV3 Menthol mainly activated the hot channel by TRPV3 and
TRPV3
TRPM8 TRPA1 Menthol mainly activated the hot channel by TRPV3 and
5 Menthol TRPV3
TRPM8 TRPA1 1 mM Menthol
the cold mainly
channel activated
by
MentholTRPM8, theand
mainly hotitchannel
canthe
activated by TRPV3
induce and
an analgesic [135,136]
5 Menthol TRPV3
TRPM8
TRPA1 TRPA1
(high) 1 mM Menthol
the mainly
cold channel activated
by TRPM8, theand
hotitchannel by TRPV3
can induce and
an analgesic [135,136]
5 Menthol TRPM8
TRPV3
TRPA1 TRPA1
(high) 1 mM Menthol
the cold
effect mainly
channel activated
hotby TRPM8,
channel
by the inhibition the
by hot
and
TRPV3
of TRPA1. channel
it can
and by
induce
the TRPV3
an and
analgesic [135,136]
5 Menthol TRPM8
TRPA1
(low) TRPA1
(high) 1 mM the cold
effect by channel by TRPM8,
the inhibition and it can induce an analgesic
of TRPA1. [135,136]
5 5 Menthol
Menthol TRPM8
TRPA1
(low) TRPA1
(high) 1
(high) mM the
1 mM cold channel by
cold TRPM8,
channel
effect by the inhibition of TRPA1.by and it
TRPM8, can induce
and it an analgesic
[135,136] [135,136]
TRPA1
(low)
TRPA1 (high) effect by the inhibition ofan
TRPA1.
(low)(low) can induce
effect by the inhibition analgesic effect
of TRPA1.
(low) by the inhibition of TRPA1.
TRPV3
6 Carvacrol TRPV3 TRPM8 0.49 ± 0.07 mM Carvacrol is rapidly desensitized by TRPA1. [63,86,136]
6 Carvacrol TRPV3
TRPA1 TRPM8 0.49 ± 0.07 mM Carvacrol is rapidly desensitized by TRPA1. [63,86,136]
6 Carvacrol TRPV3
6 Carvacrol TRPV3
6 Carvacrol TRPA1 TRPM8 0.49 ± 0.07 mM Carvacrol is rapidly desensitized by TRPA1. [63,86,136]
TRPA1
sensations of warmth in humans. 32]
TRPM8
Borneol, a common Chinese medicine, had significant

TRPV3
4 (+)-Borneol TRPA1 3.45 ± 0.13 mM analgesic and anti-inflammatory effects by activating [86,133,134]
Molecules 2023, 28, 774 TRPM8 11 of 28
TRPM8.
TRPV3
Menthol mainly activated the hot channel by TRPV3 and
Table 2. Cont. TRPM8 TRPA1
5 Menthol 1 mM the cold channel by TRPM8, and it can induce an analgesic [135,136]
TRPA1 (high)
Entry Name Structure Activate Inhibit effect
EC50 for by the inhibition
TRPV3 of TRPA1.
Description/Use Reference(s)
(low)
Molecules 2023, 28, x FOR PEER REVIEW TRPV3

TRPV3 Carvacrol is rapidly 12 of 2
6 6 Carvacrol
Carvacrol TRPM8TRPM8
0.49 ± 0.07 mM Carvacrol
0.49 ± 0.07 mM is rapidly desensitized by TRPA1. [63,86,136] [63,86,136]
Molecules 2023, 28, x FOR PEER REVIEW TRPA1
TRPA1 desensitized by TRPA1. 12 of 2
TRPV1 Carvol, isolated from oregano
TRPV1 Carvol, isolated from oregano essential oil, is a powerful
TRPV1 essential oil, is a powerful
7 7 Eugenol
Eugenol TRPV3
TRPV3 — — 2.3 mM 2.3 mM isolated from oregano essential oil, is a powerful
Carvol, [63,137] [63,137]
7 Eugenol TRPV1
TRPV3
TRPA1 — 2.3 mM vasodilator by TRPV3
vasodilator in the endothelium.
by TRPV3 in the
[63,137]
TRPA1
TRPV1 Carvol,
vasodilatorisolated from oregano
by endothelium.
TRPV3 essential
in the endothelium. oil, is a powerful
7 Eugenol TRPV1
TRPV3
TRPA1
TRPV1 — 2.3 mM Carvol, isolated from oregano essential oil, is a powerful [63,137]
7 Eugenol TRPV3
TRPV1 — 2.3 mM Carvol,
vasodilator
Carvol, isolated
by
isolated from
TRPV3
from oregano
in
oregano essential oil,
the endothelium.
essential oil, is
is a powerful
powerful [63,137]
in isaused
77 Eugenol TRPV3 — 2.3 mM [63,137]
TRPA1 TRPV1-4 vasodilator
Citral, a by Citral,
TRPV3
bioactive a bioactive
in
ingredient the ingredient
endothelium.
in lemongrass, to treat
Eugenol TRPV3
TRPV1
TRPA1
TRPV3 — 2.3 mM vasodilator by by lemongrass,
TRPV3 in in the
the endothelium. [63,137]
TRPV1 vasodilator is used to treat
8 Citral TRPA1
TRPV1
TRPA1
TRPV3
TRPV1-4
TRPM8
TRPV1-4 926 μM abnormal pain,TRPV3
Citral, a bioactive ingredient
itching or otherendothelium.
in lemongrass,
types of painisinvolving
used to treat [85]
TRPV3
TRPM8
TRPV1 TRPV1-4 Citral, abnormal pain, itching or
8 8 Citral
Citral TRPV1
TRPV3 TRPM8
TRPA1TRPM8 926 μM
TRPV1-4 926 µM a
abnormal
superficial
Citral,
bioactive
pain,
sensory
a bioactive
ingredient
itching
nerves or other
ingredient and
in lemongrass,
types of painis
inskin.
lemongrass,
used to
isinvolving
used to
treat
[85]
treat [85]
TRPM8
TRPM8
TRPV1
TRPA1
TRPV3 TRPV1-4 Citral, a other
bioactive types
ingredient of pain
in involving
lemongrass, is used to treat
8 Citral TRPM8 926
TRPA1TRPA1 926 μM
TRPV1-4 μM abnormal
superficial
Citral, pain, itching
sensory
a bioactive nerves or
ingredient other
and types
inskin. of
lemongrass, pain involving [85]
8 Citral TRPV3
TRPM8
TRPA1
TRPA1
TRPV3 TRPM8 abnormal pain, itching
superficial orsensory
other types
nervesof painisinvolving
and used to treat [85]
88 Citral
Citral TRPM8
TRPM8
TRPA1
TRPM8
TRPA1
TRPM8
TRPA1
926
926 μM μM abnormal
abnormal pain,
superficialpain, itching
sensory
superficial sensoryskin. nerves
itching
nerves
or other types
and skin.
or other of pain involving
types of pain involving
and skin.
[85]
[85]
6-tert-Butyl-m- TRPM8
TRPA1 TRPA1 superficial sensory nerves and skin.
skin.
9 TRPA1
TRPV3 TRPA1
— superficial sensory nerves and
0.37 ± 0.1 mM A much more potent TRPV3 inhibitor than camphor is. [86]
6-tert-Butyl-m-
cresol TRPA1
9 6-tert-Butyl-m- TRPV3 — 0.37 ± 0.1 mM A much more potent TRPV3 inhibitor than camphor is. [86]
6-tert-Butyl-m-
cresol
6-tert-Butyl-m- A much more potent TRPV3
9 9 TRPV3
TRPV3 — — 0.37 ± 0.1 mM A 0.1
0.37 ± muchmMmore potent TRPV3 inhibitor than camphor [86] is. [86]
9 6-tert-Butyl-m-
cresol
cresol
6-tert-Butyl-m- TRPV3 — 0.37 ± 0.1 mM A much more potent inhibitorTRPV3 inhibitor
than camphor is. than camphor is. [86]
99 cresol
cresol
TRPV3
TRPV3
TRPV3
—
— 0.37 ± 0.1 mM A much more potent TRPV3 inhibitor
0.37 ± 0.1 mM A much more potent TRPV3 inhibitor than camphor is. than camphor is. [86]
[86]
cresol A TRP channel agonist derived from thyme (thymus
10 Thymol TRPV3
TRPM8 — 0.86 ± 0.07 mM A TRP channel agonist derived from thyme (thymus [63,86,131]
10 Thymol TRPV3
TRPM8 — 0.86 ± 0.07 mM A vulgaris) and oregano
Aagonist (origanum
TRP channel vulgare).
agonist [63,86,131]
TRPA1
TRPV3
TRPV3 TRP channel
vulgaris) and oregano derived
(origanum from thyme (thymus
vulgare).
10 Thymol TRPV3
TRPM8
TRPA1
TRPV3 — 0.86 ± 0.07 mM A TRP channel agonist
derived derived
from from
thymefrom thyme (thymus
(thymus [63,86,131]
10 10 Thymol
Thymol TRPM8
TRPM8 — —0.86 ± 0.07 mM 0.86 ±A
A TRP
vulgaris)
0.07
TRP mMchannel
and
channel agonist
oregano
agonist derived
(origanum
derived thyme (thymus
vulgare).
from thyme (thymus[63,86,131] [63,86,131]
10
10 Thymol
Thymol TRPM8
TRPA1
TRPM8 —
— 0.86 ± 0.07 mM
0.86 ± 0.07 mM vulgaris)
vulgaris) and oregano
and oregano (origanum vulgare). [63,86,131]
[63,86,131]
TRPA1
TRPA1 vulgaris) and oregano (origanum vulgare).
Dihydrocarve- TRPA1 vulgaris)
A potentand TRPV3 (origanum
oregano
inhibitor vulgare).
(origanumthat isvulgare).
used as food additives
11 TRPA1
TRPV3 — 2.57 ± 0.42 mM A potent TRPV3 inhibitor that is used as food additives [86]
Dihydrocarve-
ol and artificial spices.
11 Dihydrocarve- TRPV3 — 2.57 ± 0.42 mM A potent TRPV3 inhibitor that is used as food additives [86]
11 ol
Dihydrocarve- TRPV3 — 2.57 ± 0.42 mM A and artificial
potent TRPV3spices.
inhibitor
A potent TRPV3 thatinhibitor
is used that as food additives [86]
11 Dihydrocarve-
ol
Dihydrocarve- TRPV3 — 2.57 ± 0.42 mM A A
and potent TRPV3
artificial
potent TRPV3 inhibitor
spices.
inhibitor that is
that is used
used as as food additives [86]
11 11 ol
Dihydrocarve-ol TRPV3
TRPV3 — —2.57 ± 0.42 mM 2.57 ±and0.42artificial
mM spices.
is used as food additives and food additives [86] [86]
11 ol TRPV3 — 2.57 ± 0.42 mM and artificial spices. [86]
ol and artificial
A potent TRPV3spices.
artificial spices.
inhibitor that is used as food additives
12 (-)-Carveol TRPV3 — 3.03 ± 1.16 mM A potent TRPV3 inhibitor that is used as food additives [86]
12 (-)-Carveol TRPV3 — 3.03 ± 1.16 mM A and artificial spices. [86]
and potent TRPV3
artificial inhibitor that is used as food additives
spices.
12 (-)-Carveol TRPV3 — 3.03 ± 1.16 mM A potent TRPV3 inhibitor that is used as food additives [86]
12 (-)-Carveol TRPV3 — 3.03 ± 1.16 mM A A
and potent TRPV3
artificial
spices.
A potent
inhibitorTRPV3 thatinhibitor
that is used
is used that
as food
as food additives
additives [86]
12
12 (-)-Carveol
(-)-Carveol TRPV3
TRPV3 —
— 3.03 ± 1.16 mM and artificial spices. [86]
12 (-)-Carveol TRPV3 —3.03 ± 1.16 mM 3.03 ±and1.16artificial
mM is used as food additives and
spices. [86] [86]
and artificial spices.
A non-specific TRPV channel
artificial spices. agonist that is used as an
Tetrahydrocann TRPV2 A non-specific TRPVsystem
channel agonist that is used as an
Tetrahydrocann TRPV2 anti-tumor, nervous protection,
13 abivarin TRPV3 — 3.8 ± 0.4 μM A non-specific
anti-tumor, TRPVsystem
nervous channelprotection,
agonist that is used as an [92,138,139]
13 Tetrahydrocann
abivarin TRPV2
TRPV3 — 3.8 ± 0.4 μM A immunomodulatory,
non-specific TRPV channelanti-inflammatory
agonist thatand anti-oxidant
is used as an [92,138,139]
(THCV)
Tetrahydrocann TRPV4
TRPV2 A non-specific
anti-tumor,
A non-specific TRPVsystem
nervous
immunomodulatory, TRPV channel
channel agonist that
protection,
anti-inflammatory
agonist thatand
is used
is used as an
an
anti-oxidant
as
13 Tetrahydrocann
abivarin
(THCV)
TRPV3
TRPV4
TRPV2 — 3.8 ± 0.4 μM agent.
anti-tumor, nervous system protection, [92,138,139]
13 abivarin TRPV3 — anti-tumor,
3.8 ± 0.4 μM anti-tumor, nervous system
immunomodulatory,
agent. nervous system protection, and anti-oxidant
anti-inflammatory
protection, [92,138,139]
13
13 abivarin
(THCV)
abivarin TRPV3
TRPV4
TRPV3 —
— 3.8 ±± 0.4
3.8 0.4 μM
μM immunomodulatory, anti-inflammatory and anti-oxidant [92,138,139]
[92,138,139]
(THCV) TRPV4 immunomodulatory,
agent.
immunomodulatory, anti-inflammatory
anti-inflammatory and and anti-oxidant
anti-oxidant
(THCV)
(THCV) TRPV4
TRPV4 agent.
vulgaris) and oregano (origanum vulgare).
TRPA1
Dihydrocarve- A potent TRPV3 inhibitor that is used as food additives

11 TRPV3 — 2.57 ± 0.42 mM [86]
Molecules 2023, 28, 774 ol and artificial spices. 12 of 28
Table 2. Cont. A potent TRPV3 inhibitor that is used as food additives

12 (-)-Carveol TRPV3 — 3.03 ± 1.16 mM [86]
and artificial spices.
Entry Name Structure Activate Inhibit EC50 for TRPV3 Description/Use Reference(s)
A non-specific TRPV channel
agonist
A non-specific TRPV that is used as
channel an
agonist that is used as an
TRPV2 anti-tumor, nervous system
Tetrahydrocannabivarin anti-tumor, nervous system protection,
13 2023, 28, xabivarin
13 Molecules FOR PEER REVIEW TRPV3
TRPV3 — — 3.8 ± 0.4 μM
3.8 ± 0.4 µM protection, [92,138,139] [92,138,13
13 o
Molecules 2023, 28, x(THCV)
FOR PEER REVIEW immunomodulatory, anti-inflammatory and anti-oxidant 13 of 2
Molecules 2023, 28, x FOR PEER REVIEW
(THCV) TRPV4
TRPV4 immunomodulatory, 13 of 2
agent. anti-inflammatory and
anti-oxidant agent.
TRPV1
TRPV1
TRPV1
TRPV1
TRPV2
TRPV2
TRPV2 Cannabidiol has anti-epileptic,
TRPV2 Cannabidiol
Cannabidiol hashas anti-epileptic,
anti-epileptic, immunomodulatory,
immunomodulatory,
Cannabidiol
Cannabidiol
Cannabidiol TRPV3
TRPV3
TRPV3 Cannabidiol has anti-epileptic, immunomodulatory,
immunomodulatory, analgesic,
14 14 14 Cannabidiol
(CBD)
(CBD)
TRPV3
TRPV4
TRPV4 — — — 3.73.7 ± 1.6
± 1.6 μMμM
3.7 ± analgesic,
1.6 anti-oxidation,
µM anti-oxidation,
analgesic, anti-convulsive, anti-anxiety
anti-convulsive,
anti-oxidation,
[92,140]
anti-convulsive, anti-anxiety andand [92,140]
[92,140]
14 (CBD) TRPV4 — 3.7 ± 1.6 μM analgesic,
other anti-oxidation,
effects. anti-convulsive, anti-anxiety and [92,140]
(CBD) TRPV4
TRPM8 other effects. anti-anxiety and other effects.
TRPM8
TRPM8 other effects.
TRPA1
TRPM8
TRPA1
TRPA1
TRPA1
Synthetic
SyntheticSynthetic
compounds compounds
compounds
Synthetic compounds
2- 2- 2-APB can activate TRPV1,
2-
2- TRPV1
TRPV1 TRPC1-6
TRPC1-6 2-APB
2-APB cancan activate
activate TRPV1,
TRPV1, TRPV2
TRPV2 and
and TRPV3
TRPV3 at higher
at higher
Aminoethoxydi
Aminoethoxydi TRPV1
TRPV1 TRPC1-6
TRPC1-6 TRPV2
2-APB can activate and TRPV3
TRPV1, TRPV2at higher
and TRPV3 at higher
Aminoethoxydiphenyl
15 15 15 Aminoethoxydi
phenyl borate
TRPV2
TRPV2
TRPV2 TRPM7
TRPM7 TRPM7 28 28μMμM 28 concentrations,
concentrations,
µM and and it inhibits
it inhibits
concentrations, theitthe
and IP3IP3 receptor
receptor
inhibits andand
TRPTRP
[96] [96]
[96]
15 borate
phenyl borate TRPV2 TRPM7 28 μM concentrations, and it inhibits the IP3 receptor and TRP [96]
phenyl borate TRPV3
TRPV3
TRPV3 TRPM8
TRPM8 TRPM8 channels.
channels. the IP3 receptor and TRP
(2-APB)
(2-APB)
(2-APB) TRPV3 TRPM8 channels.
(2-APB) channels.
TRPV1
TRPV1
Diphenylborini
Diphenylborini TRPV1
TRPV2
TRPV2
Diphenylborinic
16 16 c anhydride
c anhydride TRPV2
TRPV2
TRPV3 —— 85.1
85.1 μMμM 2-APB
2-APB structural
structural analogue.
analogue. [115]
[115]
16 16 c anhydride
anhydride TRPV3 — — 85.1 μM 2-APB
85.1 µM structural analogue.
2-APB structural analogue. [115] [115]
(DPBA)
(DPBA) TRPV3
TRPV3
(DPBA)
(DPBA) TRPV4
TRPV4
TRPV4
TRPV4
2-APB
2-APB structural
structural analogue
analogue that
that cancan improve
improve TRPV3
TRPV3
17 17 Drofenine
Drofenine TRPV3
TRPV3 —— 207207
μMμM 2-APB structural analogue that can improve TRPV3
selectivity.
[100]
[100]
17 Drofenine TRPV3 — 207 μM selectivity. [100]
selectivity.
Endogenous
Endogenous substances
substances
18 18 FPPFPP —— 0.13
0.13 μMμM The
The first
first endogenous
endogenous TRPV3
TRPV3 activator.
activator. [35]
[35]
18 FPP — 0.13 μM The first endogenous TRPV3 activator. [35]
A pleiotropic
A pleiotropic cellular
cellular signaling
signaling molecule
molecule that
that cancan activate
activate
19 19 Nitric
Nitric oxide
oxide NO
NO —— NANA A pleiotropic cellular signaling molecule that can activate [102]
[102]
2- TRPV1 TRPC1-6 2-APB can activate TRPV1, TRPV2 and TRPV3 at higher
Aminoethoxydi TRPV1 TRPC1-6 2-APB can activate TRPV1, TRPV2 and TRPV3 at higher
15 Aminoethoxydi TRPV2 TRPM7 28 μM concentrations, and it inhibits the IP3 receptor and TRP [96]
15 phenyl borate TRPV2 TRPM7 28 μM concentrations, and it inhibits the IP3 receptor and TRP [96]
phenyl borate TRPV3 TRPM8 channels.
(2-APB) TRPV3 TRPM8 channels.
(2-APB)
Molecules 2023, 28, 774 13 of 28
TRPV1
16 c anhydride TRPV2 — 85.1 μM 2-APB structural analogue. [115]
16 c anhydride
Table 2. Cont. TRPV3 — 85.1 μM 2-APB structural analogue. [115]
(DPBA) TRPV3
(DPBA) TRPV4
Entry Name Structure TRPV4
Activate Inhibit EC50 for TRPV3 Description/Use Reference(s)
2-APB structural analogue

2-APB that
structural can improve
analogue that TRPV3
17 17 Drofenine
Drofenine TRPV3
TRPV3 — — 207 μM 2072-APB
µM structural analogue that can improve TRPV3[100] [100]
17 Drofenine TRPV3 — 207 μM selectivity. can improve TRPV3 selectivity. [100]
selectivity.
Endogenous
Endogenous substancessubstances
18 FPP — 0.13 μM The first endogenous
The first TRPV3 activator.
endogenous TRPV3 [35]
18 18 FPP
FPP — — 0.13 μM 0.13The
µM first endogenous TRPV3 activator. [35] [35]
activator.
A pleiotropic cellular signaling molecule that can activate
19 Nitric oxide NO — NA A pleiotropicAcellular signaling
pleiotropic cellular molecule
signaling that can activate [102]
19 Nitric oxide NO — NA TRPV3 through cysteine nitrosation. [102]
Molecules 2023, 28, x FOR PEER REVIEW TRPV3 through cysteine
molecule thatnitrosation.
can activate 14 of 27
19 Nitric oxide NO — NA [102]
TRPV3 through cysteine
nitrosation.
Table 3. TRPV3 antagonists.
Table 3. TRPV3 antagonists.
Entry Name Structure Activate Inhibit IC50 for TRPV3 Description/Use Reference(s)
Natural compounds
Natural compounds
Citrusinine II can
Citrusinine IIselectively
can selectively
inhibit inhibit
TRPV3 TRPV3 and
and reduce itchy
1 1 Citrusinine II
Citrusinine II —
— TRPV3TRPV3 12.43 μM 12.43reduce
µM itchy behavior by interacting with Y564
[104] [104]
behavior by interacting
in the TRPV3with
helix.
Y564 in the TRPV3
helix.
TRPV1 Cusson, isolated from Cnidium monnieri (L.), is

2 Osthole — 37.0 ± 1.9 μM [105,141]
TRPV3 used as an antipruritic herbal medicine.
Natural compounds
Natural compounds
Citrusinine II can selectively inhibit TRPV3 and

Molecules 2023, 28, 774 Citrusinine II can selectively inhibit TRPV3 and 14 of 28
1 Citrusinine II — TRPV3 12.43 μM reduce itchy behavior by interacting with Y564 [104]
1 Citrusinine II — TRPV3 12.43 μM reduce itchy behavior
in the TRPV3 helix. by interacting with Y564 [104]
in the TRPV3 helix.
Table 3. Cont.
TRPV1 Cusson, isolated from Cnidium monnieri (L.), is

2 Osthole — 37.0 ± 1.9 μM Cusson, isolated from [105,141]
TRPV1
TRPV3
TRPV1 Cusson,
used as isolated frommonnieri
Cnidium
an antipruritic
Cnidium herbal monnieri
medicine.
(L.), is (L.), is
2 2 Osthole
Osthole —
— 37.0 ± 1.9 μM
37.0 ± 1.9 µM [105,141] [105,141]
TRPV3TRPV3 used as an antipruritic
used as an antipruritic herbal medicine.
herbal medicine.
A TRPV3 specific
A TRPV3 specific inhibitor that can significantly
Isochlorogenic inhibitor that can
Isochlorogenic acid A TRPV3 specific inhibitor that can
3 3 —
— TRPV3
TRPV3 2.7 ± 1.3 μM reverse
2.7 ± 1.3 µM ear swelling in reverse
significantly ear significantly
dermatitis and chronic
[107] [107]
Isochlorogenic
A A
acid
3 — TRPV3 2.7 ± 1.3 μM reverse ear swelling in
swelling indermatitis
dermatitis and chronic [107]
Molecules 2023, 28,acid
pruritus.
APEER REVIEW
x FOR and chronic pruritus. 15 of 2
pruritus.
A TRPV3 specific
Isochlorogenic inhibitor that can
Isochlorogenic acid
4 4 —— TRPV3
TRPV3 0.9 ± 0.3 0.9
μM± 0.3reverse
µM earsignificantly
swelling inreverse
dermatitis
ear and chronic
[107] [107]
B
acid B swelling in dermatitis
pruritus.
and chronic pruritus.
A TRPV3 inhibitor that can significantly reduce

5 Forsythoside B — TRPV3 6.7 ± 0.7 μM [108]
acute pruritus.
Isochlorogenic A TRPV3 specific inhibitor that can significantly
Isochlorogenic A TRPV3 specific inhibitor that can significantly
4
Molecules 2023, 28,4774 Isochlorogenic — TRPV3 0.9 ± 0.3 μM reverse ear swelling in dermatitis and chronic [107]
acid B — TRPV3 0.9 ± 0.3 μM reverse ear swelling in dermatitis and chronic 15 of[107]
28
4 acid B — TRPV3 0.9 ± 0.3 μM reverse ear swelling in dermatitis and chronic [107]
acid B pruritus.
pruritus.
pruritus.
Table 3. Cont.
A TRPV3 inhibitor that can significantly reduce

5 Forsythoside B — TRPV3 6.7 ± 0.7 μM A TRPV3 inhibitor
A TRPV3that can significantly
inhibitor that reduce [108]
5 Forsythoside B — TRPV3 6.7 ± 0.7 μM acute A TRPV3 inhibitor that can significantly reduce [108]
5 5 Forsythoside
Forsythoside B B —— TRPV3
TRPV3 6.7 ± 0.7 6.7 µM pruritus.
μM± 0.7acute can
pruritus. significantly reduce [108] [108]
acute pruritus.
acute pruritus.
TRPV1
Monanchomyc TRPV1 A TRPV inhibitor
A TRPV inhibitor that is that is
isolated from the
Monanchomyc TRPV1
TRPV1 A TRPV inhibitor thattheismarine
isolated from the
6 Monanchomyc — TRPV2 3.25 μM A TRPV isolated from
inhibitor that is isolated from[112]
the [112]
6 6 Monanchomycalin
alin B B —
— TRPV2
TRPV2 3.25 μM 3.25 µM
marine sponge Monanchora pulchra. [112]
6 alin B — TRPV2 3.25 μM sponge
marine sponge Monanchora
Monanchora pulchra. [112]
alin B TRPV3
TRPV3 marine sponge Monanchora pulchra.
TRPV3 pulchra.
TRPV3
A TRPV3 inhibitor that

A TRPV3 inhibitor that relieve
can effectively can effectively relieve
7 7 Verbascoside
Verbascoside —
— TRPV3
TRPV3 14.1 ± 3.314.1 A µM
μM± 3.3 TRPV3 inhibitor that can effectively relieve
[109] [109]
7 Verbascoside — TRPV3 A TRPV3 atopic
14.1 ± 3.3 μM atopic inhibitor that can
dermatitis effectively relieve
when [109]
7 Verbascoside — TRPV3 14.1 ± 3.3 μM atopic dermatitis
dermatitis
when applied
when applied
topically.
topically. [109]
Molecules 2023, 28, x FOR PEER REVIEW appliedwhen
atopic dermatitis topically.
applied topically. 16 of 27
A moderately potent
A moderately potent
TRPV1 TRPV1
inhibitor and a inhibitor and a
TRPV1
TRPV1 minimally
minimally potent potentand
TRPV3 TRPV3
TRPA1 inhibitor
8 8 Pulchranin
Pulchranin A A —
— TRPV3
TRPV3 71.8 ± 9.471.8
μM± 9.4 µM and TRPA1 inhibitor that [110,111] [110,111]
TRPA1 that is isolated from marine
is isolated sponge Monanchora
from marine
TRPA1
pulchra. sponge Monanchora
pulchra.
A moderately potent TRPV1 inhibitor and a
TRPV1
minimally potent TRPV3 and TRPA1 inhibitor
9 Pulchranin B — TRPV3 117.9 ± 11.8 μM [110]
that is isolated from marine sponge Monanchora
TRPA1
pulchra.
A moderate potent TRPV1 inhibitor and a
TRPV1
minimally potent TRPV3 and TRPA1 inhibitor
Molecules
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2
Molecules 2023, 28, 774 16 of 28
A moderately potent TRPV1 inhibitor and a

TRPV1 A moderately potent TRPV1 inhibitor and a
TRPV1 AA moderately
minimally potent
moderately potent
TRPV3
and TRPA1
TRPV1 and
and aa
inhibitor
inhibitor
8 Pulchranin A3. Cont.
Table — TRPV1
TRPV3
TRPV1 71.8 ± 9.4 μM minimally potent TRPV3 and TRPA1 inhibitor [110,111]
8 Pulchranin A — TRPV3 71.8 ± 9.4 μM minimally
that
minimally potent
is isolated from
potent TRPV3
marine
TRPV3 and
and TRPA1
sponge
TRPA1 inhibitor
Monanchora
inhibitor [110,111]
Entry 88 Pulchranin
Pulchranin
Name AA Structure ——
Activate TRPV3
Inhibit 71.8
TRPA1
TRPV3 71.8±±9.4
ICμM
9.4 μM
50 forthat is isolated from
TRPV3 marine sponge Monanchora
Description/Use Reference(s) [110,111]
[110,111]
TRPA1 that
thatisisisolated
pulchra. isolatedfrom
frommarine
marinesponge
spongeMonanchora
Monanchora
TRPA1
TRPA1 pulchra. A moderately potent
pulchra.
A moderately
pulchra. TRPV1 potent TRPV1
inhibitor and a inhibitor and a
TRPV1 A moderately potent TRPV1 inhibitor and a
TRPV1TRPV1 AA moderately
minimally minimally
potent
moderately potent
potent
TRPV3
potent TRPV3
TRPV1
and
TRPV1 inhibitor
TRPA1 and
and aa
inhibitor
inhibitor
9 9 Pulchranin
Pulchranin BB —— TRPV1
TRPV3
TRPV3 117.9 ± 11.8
TRPV1 μM
117.9 ±minimally
11.8 µM potent TRPV3
and TRPA1 and TRPA1
inhibitor that inhibitor
[110] [110]
9 Pulchranin B — TRPV3TRPA1117.9 ± 11.8 μM minimally
that
minimally potent
is isolated from
potent
is TRPV3
isolated marine
TRPV3
from and
and
marine TRPA1
sponge
TRPA1 inhibitor
Monanchora
inhibitor [110]
99 Pulchranin
PulchraninBB —— TRPV3
TRPV3 117.9
TRPA1 117.9±±11.8
11.8μMμMthat is isolated from marine sponge Monanchora [110]
[110]
TRPA1 that
pulchra. sponge
thatisisisolated
isolated fromMonanchora
from marine
marinesponge
spongeMonanchora
Monanchora
TRPA1
TRPA1 pulchra. pulchra.
pulchra.
A moderate potent TRPV1 inhibitor and a
pulchra.
TRPV1 A moderate Apotent moderate TRPV1
potent inhibitor and a
TRPV1 AA moderate
minimally
moderate TRPV1potent
potent TRPV3
potent TRPV1
andainhibitor
TRPV1
inhibitor and TRPA1 and
and aa
inhibitor
inhibitor
10 Pulchranin C — TRPV1
TRPV3
TRPV1 >200 μM minimally potent TRPV3 and TRPA1 inhibitor [110]
10 Pulchranin C — TRPV3TRPV1 >200 μM minimally
that
minimally minimally
potent
is isolated from
potent potent
TRPV3
marine
TRPV3 TRPV3
and TRPA1
sponge
and TRPA1 inhibitor
Monanchora
inhibitor [110]
10 10
10 Pulchranin
Pulchranin C CC
Pulchranin ——— TRPV3
TRPA1
TRPV3
TRPV3 >200
>200μMμM>200thatµMis isolated andfrom marine
TRPA1 sponge
inhibitor that Monanchora[110] [110]
[110]
TRPA1TRPA1 that
thatisisisolated
pulchra. isolated from
frommarine
is isolated marine
from sponge
spongeMonanchora
marine Monanchora
TRPA1
TRPA1 pulchra.
Synthetic compounds pulchra. sponge Monanchora
pulchra.
Synthetic compounds pulchra.
Synthetic
Syntheticcompounds
compounds
Synthetic compounds
Ruthenium Broad-spectrum, non-selective, cationic
11 Ruthenium — TRP(S) NA Broad-spectrum, non-selective, cationic [113]
11 Ruthenium
Red
Ruthenium — TRP(S) NA channel Broad-spectrum,
Broad-spectrum,
blockers.
Broad-spectrum, non-selective,
non-selective,cationic
cationic [113]
11 11
11 Red Red
Ruthenium ——— TRP(S)
TRP(S)
TRP(S) NA
NA channel blockers.
NA non-selective, cationic [113] [113]
[113]
Red
Red channel
channelblockers.
blockers.
channel blockers.
2,2-
2,2- TRPV1
2,2-
diphenyltetrah
2,2-
2,2- TRPV1
12 2023, — TRPV1
TRPV1
TRPV2 6–10 μM 2-APB structural
Molecules diphenyltetrah
28, x FOR PEER REVIEW
diphenyltetrahydro- TRPV1 2-APB analogue.
structural [115] 17 of 2
12 12 diphenyltetrah
ydro-furan
diphenyltetrah —
— TRPV2TRPV2 6–10 μM 6–102-APB
µM structural analogue. [115] [115]
12
12 furan
ydro-furan —— TRPV2
TRPV3
TRPV2 6–10
6–10μM
μM 2-APB
2-APB analogue.
structural
structuralanalogue.
analogue. [115]
[115]
TRPV3
ydro-furan
(DPTHF)
ydro-furan
(DPTHF) TRPV3
(DPTHF) TRPV3
TRPV3
(DPTHF)
(DPTHF)
A TRPV3 inhibitor that is
A TRPV3 obtained
inhibitorbythat is obtained by virtual
virtual
protein structure
13 13 PC5
PC5 —— TRPV3
TRPV3 2.63 ± 0.28
2.63μM protein
± 0.28 µM structure screening and lead compound
[116] [116]
screening and lead
structure optimization.
compound structure
optimization.
A TRPV3 inhibitor that is obtained by the

14 7C — TRPV3 1.05 μM [117]
bioelectron isoarrangement principle.
Molecules
Molecules2023,
2023,28,
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Molecules 2023, 28, 774

A
A TRPV3
TRPV3 inhibitor
inhibitor that
that is
is obtained
obtained by
by virtual
virtual 17 of 28
AATRPV3
TRPV3 inhibitor
inhibitorthat
thatisisobtained
obtained by
byvirtual
virtual
13
13 PC5
PC5 —
— TRPV3
TRPV3 2.63
2.63 ±± 0.28
0.28 μM
μM protein
protein structure
structure screening
screening and
and lead
lead compound
compound [116]
[116]
1313 PC5
PC5 —— TRPV3
TRPV3 2.63 ± 0.28 μM protein structure
2.63 ± 0.28 μM structure screening and lead compound
protein structure screening and lead compound [116]
[116]
structure optimization.
optimization.
Table 3. Cont. structure
structureoptimization.
optimization.
A
A TRPV3 A TRPV3 inhibitor
TRPV3 inhibitor
inhibitor that
that isis that is
obtained
obtained by
by the
the
14
14 7C
7C —
— TRPV3
TRPV3 1.05
1.05 μM
μM AA TRPV3
TRPV3 inhibitor
obtained
inhibitor that
by the
that isis obtained
obtained by
by the
the [117]
[117]
14 1414 7C7C
7C —
—— TRPV3TRPV3 1.05
TRPV3 μM 1.05bioelectron
1.05μM bioelectron
µM isoarrangement
isoarrangement
bioelectron principle.
principle. [117] [117]
[117]
bioelectron isoarrangement
bioelectron isoarrangement principle.
isoarrangement principle.
principle.

A can be used ascan local
A TRPV3
TRPV3 inhibitor
inhibitor that
that can be be used
used as
as local
local
AATRPV3
TRPV3 anesthetics
inhibitor
inhibitor thatby
that can
can bebeused
used asaslocal
local
15 15
15 Bupivacaine
Bupivacaine
Bupivacaine —
—— TRPV3 0.17
0.17 ±± 0.04
TRPV3TRPV3 mM
0.04 0.17 anesthetics
mM± 0.04
anesthetics
mM by
by extracellular
extracellular
extracellular interactions
interactions of
interactions of their
their
[118] [118]
[118]
1515 Bupivacaine
Bupivacaine —— TRPV3
TRPV3 0.17 ± 0.04 mM anesthetics
0.17 ± 0.04 mM charged
anesthetics by
by
of
extracellular
extracellular
their charged
interactions of
interactions
forms oftheir
their [118]
[118]
charged forms
forms with
with the
the TRPV3
TRPV3 channel
channel pore.
pore.
charged
chargedforms with
with
forms thethe
with theTRPV3
TRPV3 channel
channelpore.
channel
TRPV3 pore.
pore.

can be used as local
A
A TRPV3
TRPV3 inhibitor
inhibitor that
that
anesthetics
can
can be
by can be used
used as
as local
local
AATRPV3
TRPV3 inhibitor
inhibitor that
that can bebeused
used asaslocal
local
16 16
16 Mepivacaine
Mepivacaine
Mepivacaine —
—— TRPV3
TRPV3TRPV31.4
1.4 ±± 0.3 1.4 ± 0.3
0.3 mM
mM anesthetics
mM
anesthetics by extracellular
extracellular
by extracellular interactions
interactions of
interactions of their
[118]
their [118]
[118]
1616 Mepivacaine
Mepivacaine —— TRPV3
TRPV3 1.4 ± 0.3 mM anesthetics
1.4 ± 0.3 mM charged
anesthetics by
of
byextracellular
their charged
forms of
interactions oftheir
their [118]
[118]
charged forms
forms with
with
with
the
the
thethe
TRPV3
TRPV3
TRPV3 channel
channel pore.
channel pore.
charged
chargedforms
forms with
with theTRPV3
TRPV3 channel
channelpore.
pore.
pore.
A
A TRPV3
TRPV3 inhibitor
inhibitor that
thatascan
can be used localbe
can be used
used as
as local
local
AATRPV3
TRPV3 inhibitor
inhibitor that
that cancan bebeused
used asaslocal
local
17
17 Lidocaine
Lidocaine —
— TRPV3
TRPV3 2.5
2.5 ±± 0.5
0.5 mM
mM anesthetics
anesthetics byanesthetics by
by extracellular
interactions of
of their
their [118]
[118]
17 1717 Lidocaine
Lidocaine
Lidocaine —
—— TRPV3TRPV3
TRPV3 2.5 ± 0.5 mM
2.5 ± anesthetics
0.5
2.5 ± 0.5 mM charged mM by extracellular
extracellular
anesthetics bywith interactions
interactions
extracellular of
interactions their
[118]
of their [118]
[118]
charged forms
formsof with the
the TRPV3
TRPV3
their charged formschannel
channel pore.
pore.
charged
chargedforms
forms with the theTRPV3 channel
channelpore.
withwith
the TRPV3 TRPV3
channel pore.
pore.
Molecules 2023, 28, 774 18 of 28
Molecules 2023, 28, x FOR PEER REVIEW

Table 3. Cont. 18 of 27
Molecules
Molecules 2023,
Molecules 2023, 28,
2023, 28, xxx FOR
28, FOR PEER
FOR PEER REVIEW
PEER REVIEW
REVIEW 18
18 of
18 of 27
of 27
27
A TRPV3 inhibitor that can be used as local
anesthetics
A TRPV3 inhibitor by can be used as local
that
18 18 Ropivacaine
Ropivacaine —
— TRPV3TRPV3
0.28 ± 0.04 0.28 A
A TRPV3
mM± 0.04TRPV3
anesthetics
A TRPV3
mM inhibitor
inhibitor
by that
extracellular
inhibitor that
extracellular can be
be used
thatinteractions
can used as
interactions
local
of their
as local
[118] [118]
18 Ropivacaine — TRPV3 0.28 ± 0.04 mM anesthetics by of extracellular
their charged interactions of their
forms [118]
18
18
18 Ropivacaine
Ropivacaine
Ropivacaine —
—
— TRPV3
TRPV3
TRPV3 0.28
0.28 ±±± 0.04
0.28 0.04 mM
0.04 mM anesthetics
mM charged
anesthetics
forms
anesthetics by
by extracellular
by extracellular
with the TRPV3
interactions
interactions of
of their
of their
channel pore.
their [118]
[118]
[118]
charged formswith the TRPV3
with channel
the TRPV3 channel pore.
charged
charged forms
charged forms
forms with
with the
with
pore. the TRPV3
the TRPV3 channel
TRPV3 channel pore.
channel pore.
pore.
A TRPV3 inhibitor that canthat
A TRPV3 inhibitor ameliorate the
A TRPV3 inhibitor that can ameliorate the
19 Dyclonine — TRPV3 3.2 μM A
A TRPV3
hyperactivitycan ameliorate
TRPV3 inhibitor
inhibitor
causedthat the
can
can ameliorate
that by ameliorate the
the
itch/scratching [119]
A TRPV3 inhibitor that can ameliorate the
19 19 Dyclonine
Dyclonine — TRPV3
TRPV3 3.2 μM hyperactivity
3.2 µM caused caused
hyperactivity by byitch/scratching
[119] [119]
19
19
19 Dyclonine
Dyclonine
Dyclonine —
—
— TRPV3
TRPV3
TRPV3 3.2
3.2 μM
3.2 μM
μM hyperactivity caused
caused by
hyperactivityitch/scratching
behaviors.
hyperactivity caused by itch/scratching
by itch/scratching
itch/scratching [119]
[119]
[119]
behaviors.
behaviors.
behaviors. behaviors.
behaviors.
Example #64 A TRPV3 inhibitor
A TRPV3 inhibitor discovered by Hydra
Example #64 A TRPV3 discovered
inhibitor by discovered
Hydra by Hydra
20 Example
(WO #64
Example
Example #64
#64 — TRPV3 0.2–1 μM A TRPV3
A TRPV3
Biosciences
A inhibitor
TRPV3 thatinhibitor discovered
can reduce
inhibitor discovered
heat
discovered by
by Hydra
Hydra
sensitivity
by after
Hydra [121]
20 (WO#64 — TRPV3 0.2–1 μM Biosciences that can
Biosciences that can reduce heat sensitivity after [121]
Example
20 20
20
20 (WO
(WO
2006/122156)
(WO —
—
—
— TRPV3
TRPV3
TRPV3TRPV3 0.2–1
0.2–1 μM
0.2–1 μM Biosciences
μM 0.2–1
Biosciences
µM
carrageenan
Biosciences that
that can
reduce
injection
that can reduce
canheat
reduce heat
heatorsensitivity
insensitivity
burns
reduce heat sensitivity
hind paws.
sensitivity after
after
[121]
after [121]
[121]
[121]
(WO 2006/122156)
2006/122156) carrageenanafter
injection in burns or hind paws.
carrageenan
2006/122156)
2006/122156)
2006/122156) carrageenan
carrageenan injection
carrageenan injection in
injection in burns
burns or
or hind
hind paws.
paws.
injection ininburns
burnsor or hind
hind paws.
paws.
DCP-THQ
DCP-THQ A TRPV3 inhibitor discovered by Hydra
21 DCP-THQ
DCP-THQ
(WO
DCP-THQ — TRPV3 117 nM A TRPV3 inhibitor discovered by Hydra [123]
21 (WO — TRPV3 117 nM A
A TRPV3
TRPV3 inhibitor
inhibitor
Biosciences.
A TRPV3 discovered
A TRPV3
inhibitor inhibitor by
discovered
discovered by Hydra
by Hydra
Hydra [123]
21
21 DCP-THQ
(WO
(WO
2007/056124) —
— TRPV3
TRPV3 117 nM
117 nM
nM 117 Biosciences. [123]
[123]
21 21 (WO —
— TRPV3TRPV3 117 nM
Biosciences. discovered by Hydra [123] [123]
(WO2007/056124)
2007/056124) Biosciences.
Biosciences.
2007/056124)
2007/056124) Biosciences.
2007/056124)
Example #19
Example #19
Example
(US #19
Example
Example #19
#19
22 (US — TRPV3 200–1000 nM A TRPV3 inhibitor discovered by Glenmark. [124]
22 Example
(US #19
(US
2010/0292554A — TRPV3 200–1000 nM A TRPV3 inhibitor discovered by Glenmark. [124]
22 (US — TRPV3 A TRPV3 inhibitor by
22 22
22 2010/0292554A
(US —
—
— TRPV3
TRPV3TRPV3200–1000
200–1000 nM
200–1000 nM A
A TRPV3
200–1000
nM A TRPV3
nM
TRPV3 inhibitor
inhibitor
inhibitor discovered
discovered
discovered by Glenmark.
by Glenmark. [124]
Glenmark. [124]
[124]
[124]
2010/0292554A
2010/0292554A
1) discovered by Glenmark.
2010/0292554A
2010/0292554A1)
1)
1)
1)
1)
Example #58
Example #58
Example
(US #58
Example
Example #58
#58
23 (US — TRPV3 < 500 nM A TRPV3 inhibitor discovered by Glenmark. [125]
23 (US
(US
2009/0286811A
(US — TRPV3 < 500 nM A TRPV3 inhibitor discovered by Glenmark. [125]
23
23
23 2009/0286811A —
—
— TRPV3
TRPV3
TRPV3 <<< 500
500 nM
500 nM
nM A
A TRPV3
A TRPV3 inhibitor
TRPV3 inhibitor discovered
inhibitor discovered by
discovered by Glenmark.
by Glenmark.
Glenmark. [125]
[125]
[125]
2009/0286811A
2009/0286811A
1)
2009/0286811A
1)
1)
1)
1)
21 (WO — TRPV3 117 nM [123]
Biosciences.
2007/056124)
Molecules 2023, 28, 774 Example #19 19 of 28
(US
22 — TRPV3 200–1000 nM A TRPV3 inhibitor discovered by Glenmark. [124]
2010/0292554A
Table 3. Cont.
1)
Example #58
Example
(US #58 A TRPV3 inhibitor
23 23 2023,
Molecules
Molecules 2023,28,
28,x xFOR PEER
(US
FOR PEERREVIEW
REVIEW —
— TRPV3TRPV3 < 500 nM < 500
AnM
TRPV3 inhibitor discovered by Glenmark. [125] [125]1919ofof2727
Molecules 2023, 2009/0286811A
28, x FOR PEER REVIEW discovered by Glenmark. 19 of 27
2009/0286811A1)
1)
Example
Example#58
#58
Example #58
24
24 (WO
Example
(WO#58 —
— TRPV3
TRPV3 <250
<250nM AATRPV3
nM <250 TRPV3inhibitor
A TRPV3
inhibitordiscovered
inhibitor by
discovered byGlenmark.
Glenmark.[126] [126]
[126]
24 24 (WO —
— TRPV3TRPV3 <250 nM AnM
TRPV3 inhibitor discovered by Glenmark. [126]
(WO 2009/130560)
2009/130560) discovered by Glenmark.
2009/130560)
2009/130560)
Example
Example#23
#23
Example #23
25 Example
(WO #23 — TRPV3 A TRPV3 inhibitor by Glenmark.
25 25
25 (WO
(WO —
— TRPV3TRPV3 <50
TRPV3 <50nM
<50 nM <50A
nM AA
TRPV3
nMTRPV3inhibitor
TRPV3 inhibitordiscovered
inhibitor discoveredby
discovered byGlenmark.
[127]
[127]
(WO 2010/055384) discovered by Glenmark.
2010/055384)
2010/055384)
2010/055384)
Example
Example#7#7
Example #7
26 26
26 (US2010/01521
(US2010/01521 —
—
— TRPV3TRPV3 <100
TRPV3 <100nM AAnM
nM <100 TRPV3
TRPV3inhibitor
inhibitordiscovered
discoveredby
byGlenmark.
[128]
26 (US2010/0152192)
(US2010/01521 — TRPV3 <100 nM A TRPV3 discovered
inhibitor by Glenmark.
discovered by Glenmark. [128]
92)
92)
92)
Example
Example#37
#37
Example #37
27
27 (US2010/01521
(US2010/01521 —
— TRPV3
TRPV3 <100
<100nM
nM AATRPV3
TRPV3inhibitor
inhibitordiscovered
discoveredby
byGlenmark.
Glenmark. [128]
[128]
27 (US2010/01521 — TRPV3 <100 nM A TRPV3 inhibitor discovered by Glenmark. [128]
Example #7
Molecules 2023, 28, 774 20 of 28
26 (US2010/01521 — TRPV3 <100 nM A TRPV3 inhibitor discovered by Glenmark. [128]
92)
Table 3. Cont.
Molecules 2023,Example #37 REVIEW

28, x FOR PEER 20 of 27
27 27 2023, (US2010/01521
Molecules 28, x FOR PEER REVIEW —
— TRPV3TRPV3 <100 nM <100AnM
TRPV3 inhibitor discovered by Glenmark. [128] [128]20 of 27
(US2010/0152192) discovered by Glenmark.
Molecules 2023, 28, x 92)
FOR PEER REVIEW 20 of 27
Example #83
28 (WO2010/0731
Example #83 — TRPV3 <50 nM A TRPV3 inhibitor discovered by Glenmark. [129]
28 28)
Example #83
(WO2010/0731 — TRPV3 <50 nM A TRPV3 inhibitor discovered by Glenmark. [129]
28 28 (WO2010/0731
28) —— TRPV3
TRPV3 <50 nM <50 nM
A TRPV3 inhibitor discovered by Glenmark.[129] [129]
(WO2010/073128) discovered by Glenmark.
28)
A high potent TRPV3 inhibitor discovered by

29 74a — TRPV3 0.38 μM A high potent TRPV3
AGlenmark
high potentthat
TRPV3caninhibitor
be effective in by
discovered rat [130]
inhibitor discovered by
29 29 74a
74a —
— TRPV3TRPV3 0.38 μM neuropathic
0.38Glenmark
µM pain
A high potent
that model.
TRPV3
can
Glenmark inhibitor
be
that be discovered
caneffective in ratby
[130] [130]
29 74a — TRPV3 0.38 μM effective
Glenmark pain in rat be effective
thatmodel.
can in rat [130]
neuropathic
neuropathic pain model.
neuropathic pain model.
Endogenous substance
An endogenous
An endogenous TRPV3 of
TRPV3 inhibitor
30 30 17R-RvD1
17R-RvD1 —
— TRPV3
TRPV3 0.4 μM 0.4 µM inhibitor of endogenous [142] [142]
endogenous
An endogenouslipid
lipid metabolites.
TRPV3 inhibitor of
metabolites.
30 17R-RvD1 — TRPV3 0.4 μM An endogenous TRPV3 inhibitor of [142]
endogenous lipid metabolites.
30 17R-RvD1 — TRPV3 0.4 μM [142]
endogenous lipid metabolites.
Isopentenyl
TRPV3 An endogenous TRPA1 and TRPV3 inhibitor for
31 pyrophosphate
Isopentenyl — 0.24 μM [143]
TRPA1
TRPV3 topical
An analgesia.
endogenous TRPA1 and TRPV3 inhibitor for
31 (IPP)
Isopentenyl
pyrophosphate — 0.24 μM [143]
TRPV3
TRPA1 topical analgesia. TRPA1 and TRPV3 inhibitor for
An endogenous
31 pyrophosphate
(IPP) — 0.24 μM [143]
TRPA1 topical analgesia.
Molecules 2023, 28, 774 21 of 28
An endogenous TRPV3 inhibitor of

30 17R-RvD1 — TRPV3 0.4 μM [142]
Table 3. Cont. endogenous lipid metabolites.
Isopentenyl
Isopentenyl TRPV3TRPV3 An TRPA1
An endogenous endogenous
and TRPA1
TRPV3 inhibitor for
31 31 pyrophosphate
pyrophosphate —
— 0.24 μM 0.24 µM and TRPV3 inhibitor for [143] [143]
(IPP) TRPA1TRPA1 topical analgesia.
topical analgesia.
(IPP)
Molecules 2023, 28, 774 22 of 28
4. Conclusions
In summary, the TRPV3 channel is a Ca2+ -permeable nonselective cation channel.
TRPV3 is widely distributed in various organs, including the brain, skin, colon, testis, heart,
lung and liver. It has six transmembrane domains, and it forms a tetramer complex. A
large number of scientists are studying TRPV3’s role in health and disease. The current
studies have revealed that TRPV3 plays a regulatory role in temperature perception, pain
transduction, skin physiology, inflammation, cancer and cardiac hypertrophy. TRPV3
channels also play a critical role in skin physiology, including skin barrier formation, hair
growth, wound healing, Olmsted syndrome, skin pain and itching. The TRPV3 channel
is a potential target for the treatment of itching and skin-related disorders. It is of great
significance to search and screen for highly selective TRPV3 activators and inhibitors for
beneficial pharmacological interventions for related diseases.
Initially, the activators and inhibitors of TRPV3 were mostly found in extracts of
natural products. Early TRPV3 modulators were discovered by accident. Due to the
lack of a clear protein structure, the binding site and binding strength of the targeted
compounds to TRPV3 were not clear. A recent analysis of the spatial structure of the
TRPV3 and ligand complexes provides important guidance for further the rational design
and discovery of TRPV3 modulators with high affinity and high selectivity. Through
structure-based virtual screening, a series of TRPV3 inhibitors have been designed to
accelerate the development of TRPV3 modulators. In addition, TRPV3 has proven to be a
highly attractive pharmaceutical target, and several pharmaceutical companies have shown
intensive interest in the development of TRPV3 inhibitors.
Though many different approaches have arisen to search for TRPV3 modulators, there
are still no commercial drugs of TRPV3 modulators on the market. The reasons for this
phenomenon may be: (1) there are some differences in the distribution of drug targets
between animals and humans, the mechanism of disease occurrence is not clear, and the
mechanism of drug action needs to be improved; (2) the target selection of the drugs is not
specific, and it is easy to produce adverse reactions. We need to further improve the method
ion channel cloning and screening, refine the molecular theoretical basis of target selectivity
and explore the underlying mechanism between specific ion channels and diseases. It lays
a foundation for the development of new clinical drugs with TRPV3 regulation and the
future study of the physiological function of TRPV3.
Author Contributions: Investigation W.S.; data curation, W.S. and X.Q.; writing—original draft
preparation, W.S. and X.H.; writing—review and editing W.S., X.Q., W.W., S.H., K.L. and X.H.;
supervision, X.H.; project administration, X.H. All authors have read and agreed to the published
version of the manuscript.
Funding: This work was partially supported by grants from NSFC (82273796, 82111530209), Special Funds
for Guiding Local Science and Technology Development of Central Government (XZ202202YD0021C,
XZ202102YD0033C, XZ202001YD0028C), the Fundamental Research Funds for the Central Universi-
ties, and Graduate High-level Talent Training Program of Tibet University (2020-GSP-B019).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the extracts are available from the author.
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molecules

Keywords: TRPV3; structure; diseases; agonists; antagonists

Molecules 2023, 28, 774. https://doi.org/10.3390/molecules28020774 https://www.mdpi.com/journal/molecules

TRPV subfamily: The

Molecules 2023, 28, 774 3 of 28

Figure 2. The similarity between TRPV1-6.

Diseases Research Evidence Reference(s)

2.1. Skin Diseases

Molecules 2023, 28, 774 5 of 28

3. Small-Molecule TRPV3 Modulators

3.1. TRPV3 Agonists

mechanisms, including modulating TRPV3 and the pro-inflammatory transcription factor

3.1.2. Synthetic Compounds

3.1.3. Endogenous Substances

3.2. TRPV3 Antagonists

3.2.2. Synthetic Compounds

compound, 2,6-dimethoxy-n-(4-(trifluoromethyl)phenyl)oxazol-2-ylbenzamide, by per-

3.2.3. Endogenous Substances

Table 2. TRPV3 agonists.

A TRPV3 agonist, isolated

Borneol, a common Chinese medicine, had significant

Molecules 2023, 28, x FOR PEER REVIEW TRPV3

Dihydrocarve- A potent TRPV3 inhibitor that is used as food additives

Table 2. Cont. A potent TRPV3 inhibitor that is used as food additives

2-APB structural analogue

TRPV1 Cusson, isolated from Cnidium monnieri (L.), is

Citrusinine II can selectively inhibit TRPV3 and

TRPV1 Cusson, isolated from Cnidium monnieri (L.), is

A TRPV3 inhibitor that can significantly reduce

A TRPV3 inhibitor that can significantly reduce

A TRPV3 inhibitor that

A moderately potent TRPV1 inhibitor and a

A TRPV3 inhibitor that is obtained by the

Molecules 2023, 28, 774

A TRPV3 inhibitor that

A TRPV3 inhibitor that

Molecules 2023, 28, x FOR PEER REVIEW

Molecules 2023, 28, 774 Example #19 19 of 28

Molecules 2023,Example #37 REVIEW

A high potent TRPV3 inhibitor discovered by

Molecules 2023, 28, 774 21 of 28

An endogenous TRPV3 inhibitor of

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