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org/jmc Perspective

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug

Therapies
Tingting Hu, Jifa Zhang, Jiaxing Wang, Leihao Sha, Yilin Xia, Tyler C. Ortyl, Xiaohe Tian, and Lei Chen*

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ABSTRACT: Epilepsy is a common disease of the nervous system

characterized by transient brain dysfunction caused by an abnormal
electrical discharge from the brain neurons. The pathogenesis of epilepsy
Downloaded via ZHEJIANG UNIV on February 27, 2024 at 14:02:48 (UTC).

is complex and remains elusive. Nowadays, drug therapy is the mainstay

method for the treatment of epilepsy. More than 30 antiseizure drugs
(ASDs) were approved for clinical use. Unfortunately, about 30% of
patients still display pharmacoresistance against ASDs. The long-term use
of ASDs may cause adverse effects, raise tolerability concerns, bring
unexpected drug interactions, generate withdrawal symptoms, and
increase the economic burden. Thus, the research uncovering more
effective ASDs that are safe is still a difficult and urgent task. In this
Perspective, we describe the pathogenesis, clinical trials, and drug therapy
progress of epilepsy, focusing on summarizing the current situation of
small-molecule drug candidates progressing in epilepsy therapy, which provides future directions for the development of more
promising ASDs.

1. INTRODUCTION specific drug-resistant focal epilepsy by removing the area of

Epilepsy is a chronic neurological disease caused by an
abnormal discharge of brain neurons. Spontaneous recurrent
seizures (SRS) are the hallmark of epilepsy.1 The main clinical
symptoms of epilepsy include convulsions, loss of conscious-
ness, myoclonus, hypotonia, and prolonged duration of muscle
contraction.2 Based on the 2017 International League Against
Epilepsy (ILAE) latest definition, epilepsy is mainly divided
into focal epilepsy, generalized epilepsy, combined generalized
and focal epilepsy, and unknown epilepsy.2 Epilepsy, with a
worldwide prevalence of 0.5−1.0%, can occur in people of any
age, region, and race, but it is more common in children and
adolescents.3 Etiology of epilepsy can be due to genetics,
acquired brain injury, infection, and metabolic or immune
disorders.2 The pathogenesis of epilepsy has not been
completely elucidated and is considered closely related to
ion channels, neurotransmitter imbalance, inflammation, and
immune abnormalities.4,5 Therefore, strengthening the explo-
ration of the pathogenesis of epilepsy will help provide the
necessary theoretical basis for its diagnosis, prevention, and
treatment.
Drug therapy, surgery, and ketogenic diets are the classic
methods for treating of epilepsy. The ketogenic diets refer to
high-fat, low-carbohydrate, and moderate-protein diets, which
have been used for decades to treat drug-resistant epilepsy
(DRE). Although the antiepileptic mechanism is still unclear,
its efficacy and safety have reached a consensus.6 Epilepsy
surgery can achieve long-term seizure freedom in patients with
the seizure focus. However, it is hurdled by the risks and
postoperative complications.7 Nowadays, drug therapy is the
mainstay method for treating epilepsy, which can effectively
control seizures.8 More than 30 antiseizure drugs (ASDs, also
referred to as anticonvulsants and antiepileptic medications)
have been approved for clinical use. New ASDs such as
brivaracetam, cannabidiol, cenobamate, everolimus, and
fenfluramine have high efficacy, few adverse reactions, and
low drug resistance. However, long-term efficacy and safety
need to be further verified.9 Unfortunately, about 30% of
patients respond poorly to existing ASDs that may develop into
treatment-resistant epilepsy.10 Therefore, more effective ASDs,
particularly with reduced side effects and novel mechanisms of
action, are still in high demand for patients with DRE.
Herein, we summarize the pathogenesis, clinical trials, and
drug therapy progress of epilepsy, focusing on small-molecule
compounds with potential antiepileptic effects developed in
the past five years.
Received: December 2, 2022
Published: April 4, 2023

© 2023 American Chemical Society https://doi.org/10.1021/acs.jmedchem.2c01975

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Figure 1. Diagram for the pathogenesis of epilepsy, including abnormal ion channel function, imbalance of neurotransmitter secretion, irregular
glial system, neuroinflammation and oxidative stress, and abnormal neural circuits.
2. THE PATHOGENESIS OF EPILEPSY
Although the pathogenesis of epilepsy is complex, researchers
are gradually unraveling its mystery. Seizures are due to an
imbalance of excitatory and inhibitory neuronal firing, which is
closely related to abnormal ion channel function, imbalance of
neurotransmitter secretion, irregular glial system, neuro-
inflammation and oxidative stress, and abnormal neural circuits
(Figure 1). A more precise understanding of resistance
mechanisms may lead to the development of more effective
and tolerated drugs.
2.1. Abnormal Ion Channel Function. Ion channels,
including voltage-gated sodium channels (VGSCs), voltage-
gated potassium channels (VGPCs), and voltage-gated calcium
channels (VGCCs), are the structural basis of neuronal
signaling. Mutations in genes encoding these ion channels
will lead to changes in ion channel functions, resulting in
genetic epilepsy.11,12
2.1.1. Voltage-Gated Sodium Channels. VGSCs play a
crucial role in generating and transmitting cellular action
potentials. Pathogenic variants in sodium channel genes
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including SCN1A, SCN2A, SCN3A, SCN8A, and SCN1B
are associated with a spectrum of epilepsy phenotypes. SCN1A
is the most common epilepsy gene identified to date, NaV1.1
encoded by SCN1A is highly expressed in inhibitory neurons.4
SCN1A-related seizure disorders encompass simple febrile
seizures (FS), generalized epilepsy with febrile seizures plus
(GEFS+), Dravet syndrome (DS), and early infantile epileptic
encephalopathy (EIEE). NaV1.2 (SCN2A) and NaV1.6
(SCN8A) show the highest expression in excitatory neurons.13
SCN2A has emerged as one of the most prominent epilepsy
genes broadly associated with seizure and neurodevelopmental
phenotypes.14 Mutations in the SCN8A cause catastrophic
EIEE13 and SCN8A developmental and epileptic encephalop-
athy (SCN8A-DEE), which are also associated with intractable
epilepsy.15 A few pathogenic SCN3A variants have been
reported in familial focal epilepsy with variable foci, as well as
in patients with early onset DEEs.16 SCN1B encodes sodium
channel β subunit (NaVβ1), which is enriched in the neuronal
axon initiation segment and node of Ranvier.17 SCN1B
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variants are associated with severe DEEs resembling DS and
GEFS+.18
2.1.2. Voltage-Gated Potassium Channels. VGPCs are
necessary in the maintenance of the cell resting membrane
potential, regulating action potential discharge, and releasing
neurotransmitters. A variety of seizure-related potassium
channel mutations have been found, such as KCNQ2,
KCNQ3, KCNA1, KCNA2, KCNB1, KCNC1, KCNMA1,
KCNT1, and KCTD7.11 KV7 (KCNQ channel) is the seventh
subfamily of VGPCs, which consists of five members (KV7.1−
7.5) that each have a different tissue distribution and
physiological function.19 KCNQ1 is restricted to cardiac
tissues,20 and KCNQ2−5 are mainly expressed in the central
and peripheral nervous systems. Therefore, they are often
referred to as neuronal KCNQs. The KCNQ2/3 hetero-
tetramer assembled by KCNQ2 and KCNQ3 subunits is the
main molecular entity of M current, which can stabilize the
resting membrane potential and limit the repetitive firing of
neurons.21 It has been confirmed that mutation-induced
reduction of KV7.2 subunit stability or changes in M current
gating may lead to the development of neonatal epilepsy.22
Therefore, neuronal KCNQ2/3 channels are important targets
for treating diseases such as epilepsy and chronic pain.23
KCNT1 encodes the sodium-activated potassium channel
KNa1.1 (Slack, Slo2.2), which is widely expressed in the CNS.24
Gain-of-function (GOF) mutations in the KCNT1 gene are
associated with DREs, including nocturnal frontal lobe epilepsy
and epilepsy of infancy with migrating focal seizures.25
2.1.3. Voltage-Gated Calcium Channels. VGCCs that
involve in the release of presynaptic transmitters, the
synchronous firing of neurons, and paroxysmal depolarization
drift, are widely distributed in various tissues and cells.26
VGCCs can be classified as high-voltage activation (L, P/Q,
and N-type) or low-voltage activation (T-type) based on the
range of membrane potentials at which the channel becomes
active.27 L-Type channels consist of the α1 subunit from the
CaV1 family, while P/Q and N-type channels consist of CaV2.1
and CaV2.2 α1 subunits, respectively.28 Low-voltage activated
T-type calcium channel (TTCC), mainly including CAC-
NA1G (Ca3.1), CACNA1H (Ca3.2), and CACNA1I (Ca3.3),
has been studied the most.29 The mice overexpressing CaV3.1
showed frequent spike discharges (a sign of absence seizure),
while knockout mice lacking CaV3.1 were protected from
absence seizure.30 Mutations in CACNA1H (CaV3.2) have
been identified in patients with idiopathic generalized epilepsy
(IGE).31 CACNA1A (CaV2.1) is a susceptible gene for the
absence of epilepsy. Abnormal CaV2.1 channel will affect
membrane excitability, calcium influx-dependent neurotrans-
mitter release, and abnormal oscillation rhythm of the loop,
eventually leading to the absence of seizure. 32 The
pharmacological studies in GAERS or WAG/Rij genetic
models have shown that T-type calcium channel blockers
significantly reduced epileptic activity.33,34
2.2. Imbalance of Neurotransmitter Secretion. Neuro-
transmitters are endogenous chemicals that are typically stored
in synaptic vesicles and axon terminals and released into the
synaptic cleft during signal transduction. They modulate
excitatory/inhibitory neuronal function by binding to their
receptors.35 The imbalance of γ-aminobutyric acid (GABA)
and glutamate secretion in neurons is closely related to
seizures.36
2.2.1. GABA. GABA is a major inhibitory neurotransmitter
in the mammalian CNS. Enhancement of GABAergic neuro-
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transmission has been shown to inhibit or attenuate seizures.37
GABA is mainly synthesized at axonal terminals, which is
formed by decarboxylate of glutamate precursor under the
action of glutamic acid decarboxylase (GAD). Synthetic GABA
is released from vesicles into the synaptic cleft via vesicular
GABA transporters after neuron depolarization. Then GABA
can bind to receptors (GABA-A, GABA-B, and GABA-C
receptors) on the postsynaptic membrane to mediate
excitatory transmission. Also, GABA can be retaken to
presynaptic neurons by GABA transporters (GATs) or
transported to glial cells, reducing its concentration in the
synaptic cleft, thus terminating the inhibitory synaptic
transmission of GABAergic. GABA is ultimately catabolic to
succinic acid semialdehyde mediated by GABA amino-
transferase (GABA-AT). Clinical studies have demonstrated
that drugs enhancing GABA-mediated inhibitory synaptic
transmission are effective in treating epilepsy.38,39 GABA
receptors (GABAR), GABA-AT, and GATs have become
important targets for the development of ASDs recently.40−42
2.2.2. Glutamate. Glutamate, the most abundant amino
acid in the brain, is transmitted between astrocytes and glial
cells to achieve rapid signaling transduction. It plays an
important role in neuronal excitability.43 Four glutamate
receptors have been identified: ionotropic glutamate receptors
(iGluR), including mammalian α-amino-3-hydroxy-5-methyl-
4-isoxazole propionic acid receptors (AMPAR), kainate
receptors (KAR) and N-methyl- D -aspartate receptors
(NMDAR), and metabotropic glutamate receptor
(mGluR).44 Studies have shown that overstimulation of
glutamate receptors will lead to glutamate accumulation,
promoting the occurrence and development of epilepsy.45
The GluA2 subunit of AMPAR is selectively permeable to Na+
and prevents Ca2+ influx. AMPAR blockers can significantly
reduce or inhibit the occurrence of epilepsy. 46 The
heteromeric GluK2/GluK5 of KARs have been shown to
significantly contribute to epileptic relapses in chronic
epilepsy.47 NMDAR is primarily permeable to Ca2+ and
important for seizure activity.48 Missense mutations in genes
encoding NMDAR have been reported to cause early onset
epilepsy and intellectual disability.49
2.3. Irregular Glial System. The glial cells in CNS mainly
include astrocytes, microglia, and oligodendrocytes.50 In recent
years, it has been found that abnormal glial cells can change the
microenvironment by altering the neurotransmitters, regulating
the switch of ion channels, promoting the release of
inflammatory factors, and changing the nerve myelin sheath,
contributing to epilepsy progression. Astrocytes are abundantly
distributed in the surrounding neurons, which play a
supporting and nutritional role. Astrocyte dysfunction destroys
the function of membrane protein (EAAT2), which is
responsible for glutamate uptake. A large amount of glutamate
accumulates outside the cell, resulting in increased neuronal
excitability, which induces epilepsy.45 Astrocytes are also major
regulators of K+ and aquaporins.51 Astrocyte dysfunction
impairs the uptake of potassium (Kir4.1) and changes the
intracellular and extracellular osmotic pressure (AQP4).52
Seizures activate many astrocytes, and those astrocytes release
inflammatory factors that further aggravate seizures.53 Micro-
glia are macrophages in CNS and play an important role in
immune functions. Under stress or pathological conditions,
excessive activation of microglia can produce oxygen free
radicals and cytokines, resulting in neuronal apoptosis and
recruitment of immune cells to attack the blood−brain barrier
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Figure 2. Diagram for the pathogenesis of DRE, including the transporter hypothesis, target hypothesis, gene variation hypothesis, intrinsic severity
hypothesis, neural network hypothesis, and pharmacokinetic hypothesis.
(BBB).54 Oligodendrocytes are the only cells that produce the
nerve myelin sheath that allows neuronal cells to perform their
conduction function. Studies have found that changes in nerve
myelin can also cause epilepsy.55
2.4. Neuroinflammation and Oxidative Stress. The
destruction of the BBB emerges when inflammatory responses
in the peripheral and central nervous systems become
activated, ultimately caused by infections, trauma, or tumors
within the brain. The damage of BBB can cause the
extravasation of serum lymphocytes, immunoglobulins, and
albumin into the CNS. Subsequently, this can cause the
activation and proliferation of glial cells, which enhances the
excitability of astrocyte nerves and eventually leads to
seizures.56 Studies have shown that the ABC efflux transporters
(P-gp, BCRP, MRP) in vascular endothelial cells can effectively
inhibit therapeutic drugs through BBB, leading to the
occurrence of refractory epilepsy and DRE.57
Neuroinflammation is associated with inflammatory media-
tors released from neurons, glial cells, and BBB endothelial
cells, including interleukin-1β(L-1β), high-mobility group box
1(HMGB1), tumor necrosis factor α (TNF-α), transforming
growth factor β (TNF-β), cyclooxygenases-2 (COX-2)−
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prostaglandin-E2 (PG-E2) axis, and activated intracellular
signaling pathways.58 Inflammatory mediators can promote the
transcriptional activation of autocrine and/or paracrine
inflammatory genes. They can also directly activate homolo-
gous receptors expressed on neurons of epileptogenic tissues,
which can alter the transcriptional activity of glutamate, GABA
receptors, and other ion channels, thereby increasing neuronal
excitability.59 After seizures or during recurrent seizures,
endogenous IL-1β and HMGB1 release are increased, which
can bind to IL-1β and TLR4 receptors to activate downstream
intracellular signaling molecules and finally induce the
transcription of inflammatory genes regulated by nuclear
factor-κ B (NF-κB).60 In epilepsy patients and animal models,
the COX-2 level in brain is up-regulated, which can induce the
conversion of arachidonic acid to PGs. Therefore, inhibition of
COX-2 or blockade of the PG receptor can protect neurons
and inhibit seizure.61 Recent studies have shown that albumin
generated by BBB damage can penetrate the intercellular space
in the brain, then activate TGF-β signaling pathway changes in
astrocytes and destroy the potassium buffering capacity and
glutamate metabolism, causing an increase in nerve excitability
and lowers the seizure threshold.62 Studies have suggested that
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a profound interaction between inflammation and epilepsy,63
which indicates blocking unwanted inflammatory signals in the
brain may provide new strategies for treating epilepsy.
Oxidative stress (OS) is oxidative damage caused by the
production of reactive oxygen species (ROS) and reactive
nitrogen species (RNS) due to mitochondrial dysfunction,
increased activities of NADPH oxidase (NOX), xanthine
oxidase, and inducible nitric oxide synthase (iNOS). Free
radicals produced by seizures can lead to OS damage and
increased the ratio of OS markers, such as iNOS oxidized and
reduced glutathione can be detected in patients with TLE.64
Endoplasmic reticulum stress (ERS) is a condition that
various physical and chemical factors (such as oxidative stress,
mutant protein expression, and abnormal Ca+ concentration)
disrupt ER function and lead to unfolded or misfolded proteins
accumulating in the ER lumen.65 Increasing studies have
suggested that abnormal ER stress may participate in various
pathological processes associated with epilepsy.66
2.5. Abnormal Neural Circuits. The pathogenesis of
epilepsy is related to the enhancement of neural network
excitability caused by abnormal synaptic connections between
brain neurons and the establishment of pathological neural
circuits. Recent studies have found that factors containing
long-term potentiation (LTP), mossy fiber sprouting (MFS),
neuropeptide Y (NPY), neural cell adhesion molecule
(NCAM), and mGluRs are involved in the occurrence and
development of epilepsy and the plasticity of the neuronal
synapse. Seizures can induce LTP production at glutamatergic
synapses in epileptic regions, which leads to persistent
remodeling between synapses.67 A variety of axon-guiding
molecules, such as semaphorins and Eprins, affect the normal
growth of axons and ultimately lead to abnormal neuronal
networks in seizures.68 MFS is the main pathological change of
temporal lobe epilepsy. It has been found that MFS projects to
glutamatergic interneurons of the dentate gyrus, leading to
increased excitability of the dentate gyrus and transmission to
the hippocampus in epileptic animal models.69 In addition,
NPYs are released in the hippocampus to bind the receptors in
granulosa cells, which can promote mossy fiber budding and
synaptic reconstruction in seizures.70
2.6. Drug-Resistant Epilepsy. The mechanism of DRE
likely involves multifactors, including environment, genetics, as
well as factors related to disease and drugs.71 Several
hypotheses have been proposed, including the transporter
hypothesis, target hypothesis, gene variation hypothesis,
intrinsic severity hypothesis, neural network hypothesis, and
pharmacokinetic hypothesis (Figure 2).72 The transporter
hypothesis and target hypothesis are the most cited theories of
ASD resistance, but neither can fully explain the neuro-
biological basis of drug resistance. 73 The transporter
hypothesis suggests that overexpression of multidrug efflux
transporters at the BBB barrier in epilepsy decreases ASD brain
uptake, thus causing ASD resistance.72,74 The best-understood
efflux transporters in epilepsy are members of the ATP-binding
cassette (ABC) superfamily, specifically P-glycoprotein (P-gp,
MDR1), the multidrug resistance-associated proteins (MRP1,
ABCC1; MRP2, ABCC2), and breast cancer resistance protein
(BCRP, ABCG2).75 Overexpression of efflux transporters in
brain capillary endothelium, astrocytes, and/or dysplastic
neurons with refractory epilepsy has been documented in
numerous studies.76 It has been suggested that inhibiting P-gp
in epileptic rats with proven drug resistance can counteract
resistance.77 However, some aspects of the transporter
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hypothesis are currently controversial, and further studies are
needed to determine the clinical relevance of efflux transporter
overexpression at the BBB.72 The target hypothesis postulates
that acquired alterations of ASD targets at molecular levels,
such as changes in voltage-gated ion channels, neuro-
transmitter receptors, transporters, or metabolic enzymes,
lead to decreased drug sensitivity to treatment.78 Remy et al.
showed that loss of use-dependent blockade of voltage-gated
Na+ channels by carbamazepine was observed in patients with
carbamazepine-resistant TLE.79 In the pilocarpine model of
epilepsy, the changes in GABAA receptor makes patients
resistant to ASDs acting through this receptor.80 Changes in
the GABAA receptor reducing drug sensitivity in patients with
refractory TLE have also been reported.81 The evidence of this
hypothesis is limited and needs to be further studied and
verified. One of the most faithful hypotheses, and possibly the
most basic cause of resistance, is the genetic variation
hypothesis, which states that variations in genes, encoding
ion channels, and neurotransmitter receptors, or enzymes that
metabolize ASDs, associated with ASD pharmacokinetics, and
pharmacodynamics cause inherent pharmacoresistance.82 The
polymorphism of the SCN1A gene may affect the con-
formation of the encoded protein or stability of post-
transcriptional miRNAs and results in the reduced response
of ASDs to sodium channel blockade, ultimately leading to
drug resistance.83 Some studies have found a strong association
between CYP2C9 polymorphism and phenytoin dose require-
ment.83,84 However, this hypothesis is limited by incon-
sistencies and poor reproducibility of study findings, more
powerful and repeatable pharmacogenomics research is needed
to prove it. The intrinsic severity hypothesis states that drug
resistance is related to the severity of epilepsy.85 The frequency
of seizures is considered to be an important indicator of the
disease severity.86 Data supporting this hypothesis suggest that
patients with more than 10 seizures before initiation of therapy
were more than twice as likely to develop refractory epilepsy.87
However, Musicco et al. reported that patients treated after the
first seizure and those who received treatment after seizure
recurrence had the same probability of achieving 1 and 2
seizure-free years.88 A randomized controlled trial found that
immediate ASD treatment can reduce seizure occurrence in
the next 1−2 years, but there was no difference in the long
term remission in individuals with single or infrequent
seizures.89 There is little evidence to prove a direct connection
between the severity of epilepsy and ASD response. Therefore,
drug resistance in epilepsy cannot be fully explained by this
hypothesis.90 The neural network hypothesis suggests that the
endogenous antiepileptic system is inhibited by degeneration
and reconstruction of the neural network (including neuro-
genesis, gliosis, neurodegeneration, axonal sprouting, and
synaptic reorganization), which inhibits ASDs from accessing
to neuronal targets.91 Molecular evidence shows that
cytoskeletal genes and cytoskeletal effectors in the growth
cone at the tip of each axon can affect growth cone steering,
were abnormally expressed in the brains of DRE patients.91,92
Before this hypothesis, it had been suggested that hippocampal
sclerosis plays an important role in the mechanisms of drug
resistance in ASD.93 This view has been confirmed in drug-
resistant patients with the resection of the affected temporal
lobe, as resection of affected tissue usually reverses drug
resistance.94 The pharmacokinetic hypothesis states that
overexpression of exogenous transporters in peripheral organs
can reduce the plasma level of ASD in patients with intractable
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Figure 3. History of ASDs development can be divided into three generations. The year of introduction refers to the first clinical use for epilepsy in
Europe, the United States, or Japan is depicted. The figure does not include drugs that are rarely used today.
epilepsy, thereby reducing the number of ASD reaching
intracerebral epileptic lesions.95 P-gp may be a barrier to
prevent drugs from the intestinal lumen into the bloodstream,
thus reducing their oral bioavailability.96 It was found that
there was no difference in plasma concentration of drugs
between ASDs responders and nonresponders in animal
epilepsy models.97 However, this hypothesis postulated by
Lazarowski et al. based on only two case studies, and it is not
clear if their observation is limited to these cases or a
widespread phenomenon, which needs to be further verified.95
Nevertheless, based on current evidence, the mechanisms of
drug resistance epilepsy are still not fully understood and
remain challenging in treating epilepsy patients.
3. CURRENT CLINICAL DEVELOPMENT STATUS
Drug therapy is the mainstay treatment for epilepsy, which can
reduce the occurrence of seizures but cannot essentially cure
the disease because of the diversity of epilepsy causes, genetic
heterogeneity, and different pathogenesis.98 Nowadays, over 30
ASDs have been approved for clinical use, which is different in
pharmacokinetics, efficacy, and adverse reactions.99 The
history of ASDs development can be divided into three
generations (Figure 3).8,100 The first generation is traditional
ASDs (before 1958), including potassium bromide, pheno-
barbital, and barbiturate analogues (phenytoin and ethosux-
imide). The second-generation ASDs were introduced between
1960 and 1975, including carbamazepine, valproate, and the
benzodiazepines. Phenytoin and valproate are still the first-line
drugs for epilepsy treatment, but other first- and second-
generation ASDs are rarely used because of obvious adverse
effects, unfavorable pharmacokinetics, and drug interaction
profiles. The era of the third-generation AEDs started in the
1980s, such as lamotrigine, levetiracetam, and oxcarbazepine.
Due to new targets and mechanisms, third-generation drugs
further reduce adverse drug reactions, improve pharmacoki-
netics and drug resistance, and have fewer drug interactions.100
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In recent years, some novel ASDs, including cannabidiol,
acetazolamide, cenobamate, and ganaxolone, were introduced
into the market. However, their clinical application time is
relatively short, and long-term efficacy and safety need to be
further verified.11
ASDs mechanisms can be divided into five categories (Table
1): (1) Modulation of voltage-gated ion channels, including
VGSCs, VGPCs, and VGCCs; (2) enhancement of GABA-
mediated inhibitory neurotransmission, through the effects on
GABAR, GATs, and GABA-ATs; (3) attenuation of glutamate-
mediated excitatory neurotransmission via acting on AMPAR
and NMDAR; (4) modulation of neurotransmitters release
through a presynaptic action; (5) mechanism-targeted agents,
such as carbonic anhydrase (CA) inhibitors and mechanistic
target of rapamycin (mTOR) inhibitors. Some ASDs may
prevent seizures by acting on multiple targets, and the
mechanisms of action of several ASDs remain elusive.101
Table 2 summarizes some drugs in clinical development as
potential treatments for epilepsy. CVL-865 (PF-06372865) is
the first α2/3/5 subtype selective GABA-positive allosteric
modulator (PAM) to undergo phase 2 clinical trials in patients
with drug-resistant focal epilepsy (NCT04244175).38 JNJ-
40411813 is a positive allosteric regulator of mGlu2. A phase 2
clinical trial is currently underway to evaluate the effect of JNJ-
40411813 combined with Levetiracetam or Brivaracetam in
treating epilepsy (NCT04836559).128 Soticlestat (TAK 935/
OV935), a specific inhibitor of cholesterol 24-hydroxylase, was
developed as a potential ASD with novel mechanisms of
action.129 Soticlestat has completed a phase 2 clinical study
(NCT03650452) evaluating its efficacy, safety, and tolerability
as an adjunctive treatment for developmental and/or epileptic
encephalopathy in children. XEN1101 is a novel positive
allosteric regulator of KV7.2−7.5 (KCNQ2−5) potassium
channels in neurons. The phase 3 clinical trials are designed to
evaluate XEN1101 as adjunctive therapy in focal-onset seizures
(FOS) (NCT05614063) and Primary Generalized Tonic-
Clonic Seizures (PGTCS) (NCT05667142). In phase 2b
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Table 1. Molecular Targets of Clinically Used ASDs

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Table 1. continued

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Table 1. continued

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Table 1. continued

Table 2. Progress in Clinical Research of ASDs

recruitment
drugs targets sponsors phase NUT identifier status condition and disease
CVL-865 (PF- GABA-A receptor Cerevel Therapeutics, 2 NCT04244175 recruiting seizures
06372865) LLC
JNJ-40411813 mGlu2 Janssen Research and 2 NCT04836559 recruiting focal onset seizures
Development, LLC
Soticlestat (TAK- cholesterol Takeda 2 NCT03650452 completed epilepsy; Dravet syndrome; Lennox−Gastaut
935/OV935) 24-hydroxylase syndrome

XEN1101 KV7.2/7.3 Xenon Pharmaceuticals 3 NCT05614063; recruiting FOS and PGTCS

(IOP-2198) Inc.
NCT05667142 not yet
recruiting

NBI-921352 NaV1.6 Neurocrine Biosciences 2 NCT05159908 recruiting focal onset seizures

(XEN901)
NCT04873869 SCN8A developmental and epileptic
encephalopathy syndrome (SCN8A-DEE)

retigabine KV7.2/7.3 GlaxoSmithKline 4 NCT01721317 terminated epilepsy

(XEN496)
Xenon Pharmaceuticals 3 NCT04639310 recruiting KCNQ2 developmental and epileptic
Inc. encephalopathy (KCNQ2-DEE)

Padsevonil SV2/GABA-A receptor UCB Biopharma SPRL 2 NCT03373383 completed DRE;

focal-onset seizures

CX-8998 CaV3 Jazz Pharmaceuticals 2 NCT03406702 completed idiopathic generalized epilepsy

Ataluren antisense oligonucleotide NYU Langone Health 2 NCT02758626 completed Dravet syndrome
(PTC124)
CDKL5 deficiency

ACT-709478 T-type calcium channel Idorsia Pharmaceuticals 2 NCT03239691 completed photosensitive epilepsy
Ltd.
EXP-100 5-HT Epygenix 2 NCT04462770 recruiting Dravet syndrome

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Figure 4. (A) The optimization process in developing compounds 3, 4, and 5. (B) Chemical structures of other reported NaV1.6 or NaV1.2
inhibitors. Compound with a docking score higher than a threshold value (−9.0 kcal/mol) was defined as an inactive compound in the virtual
screening of the database.
clinical trial, XEN1101 demonstrated a statistically significant
and dose-dependent reduction from baseline in monthly focal
seizure frequency compared to placebo (monotonic dose
response; p < 0.001). NBI-921352 (formerly XEN901), a
heterocyclic sulfonamide compound, is a novel small-molecule
selective NaV1.6 sodium channel inhibitor. The phase 2 clinical
study assesses the efficacy, safety, and pharmacokinetics of
NBI-921352 as adjunctive therapy for seizures in subjects with
SCN8A-DEE. The most common treatment-emergent adverse
events of NBI-921352 include headache, dizziness, and nausea.
Retigabine is an ASD developed for the treatment of adults
with partial-onset seizures, which is restricted in 2013
(NCT01721317) because of its ophthalmological, dermato-
logical pigmentation, and discoloration side effects. It has been
now withdrawn from the market in 2017.130 XEN496, a new
oral formulation with RTG active ingredient, is currently in
phase 3 clinical trial (NCT04639310) for the treatment of
KCNQ2-DEE. Padsevonil (UCB0942) was designed to act on
both synaptic vesicle protein 2 (SV2) and GABAA receptors.
The phase 2 clinical study has been completed to test the
efficacy and safety of adjunctive treatment of focal-onset
seizures in adults with DRE (NCT03373383). CX-8998 is an
ASD that selectively blocks the CaV3 receptor. Currently, its
phase 2 clinical trial (NCT03406702) has been completed to
investigate the effect of IGE in adolescents and adults. Ataluren
is a daily oral drug that selectively induces readthrough
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premature and abnormal stop codons, bypassing nonsense
mutations. The phase 2 clinical study (NCT02758626)
characterizes the safety profile of ataluren in patients with
CDKL5 or DS resulting from a nonsense mutation. ACT-
709478, a T-type calcium channel agonist, has completed a
phase 2 clinical trial (NCT03239691), evaluating its effect in
photosensitive epilepsy patients. EXP-100, a clemizole
analogue that binds to the 5-HT receptor, is undergoing
phase 2 studies in DS (NCT04462770). These clinical drugs
have relatively mild or moderate side effects, such as headache,
dizziness, and somnolence.131
4. SMALL-MOLECULE COMPOUNDS FOR THE
TREATMENT OF EPILEPSY
Although the discovery of ASDs has rapidly improved in recent
years, a challenge remains to prevent and cure epilepsy or to
alleviate the plight of drug-resistance in epilepsy. The screening
of compounds with antiepileptic activity is mainly based on
three different strategies: (1) Optimizing existing ASDs,
finding safer and more effective analogues or derivatives
through in vivo epilepsy models; 2) unveiling the pathogenesis
of epilepsy, finding new targets to develop new synthetic
compounds. For example, carbonic anhydrase (CA) inhibitors
and mTOR inhibitors have been favored by scientists as
antiepileptic candidates with novel mechanisms.132,133 (3)
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Screening for drugs that include ASDs or drugs for other
diseases that have been approved by the U.0.S Food and Drug
Administration (FDA) though epilepsy animal models.134
Preclinical screening of ASDs primarily depends on
establishing epileptic models in vivo. Common animal models
are divided into three categories according to different
induction methods: acute animal epilepsy model, chronic
animal epilepsy model, and genetic absence animal epilepsy
model.97 The maximal electroshock (MES) and subcutaneous
pentylenetetrazol (scPTZ) acute epilepsy models, which serve
as the gold standard for preliminary screening of ASDs, are the
most widely used. However, these two epilepsy models cannot
detect drugs for DRE and chronic spontaneous epilepsy.97 The
chronic epilepsy models can be divided into kindling epilepsy
model, persistent epilepsy model, and spontaneous epilepsy
model based on the intensity of stimulation and the severity of
the disease. The 6 Hz corneal kindling mouse model is a
medium or high throughput model of secondary generalized
epilepsy, usually for studying drug resistance. The amygdala
kindling model, because of its high sensitivity and the
observation of brain pathological changes similar to human
temporal lobe epilepsy (TLE), is also widely used in studying
epilepsy drug resistance.135 Genetic epilepsy models are often
generalized seizures, which can simulate the absence of seizures
in human genetic epilepsy diseases. The main animal strains
are GAERS, WAG/Rij rats, DAB/2J mice, and human
mutation-based mouse models such as SCN1AR1407K/+,
SCN2AA263 V/+, SCNQ2A306T/+, and SCN8AN1768D/+.136
Here, we summarize the small-molecule compounds
discovered in recent years, which are potential therapeutic
candidates against epilepsy with different mechanism of action.
4.1. Modulation of Voltage-Gated Ion Channels.
Voltage-gated ion channels play an important role in regulating
neuronal excitability and are closely related to epilepsy.137 We
summarize the small molecule compounds developed recently
to modulate voltage-gated ion channels, which may become
potential ASDs, including 10 types of sodium channel
inhibitors, 15 types of potassium channel agonists, and four
types of calcium channel blockers.
4.1.1. Sodium Channel Inhibitors. Nine isoforms of VGSCs
are known in mammals (NaV1.1 to NaV1.9). The four isoforms
(NaV1.1, NaV1.2, NaV1.3, and NaV1.6), which are mainly
expressed in the CNS, are closely related to epilepsy.138 NaV1.2
and NaV1.6 isoforms are highly expressed in excitatory
neurons, while NaV1.1 is mainly expressed in inhibitory
neurons.139 NaV inhibitors, such as phenytoin, carbamazepine,
lamotrigine, and oxcarbazepine, have been used for decades as
anticonvulsants for the treatment of epilepsies.140 However,
these existing NaV inhibitors have no selectivity in the nine
sodium channel isoforms, require a large number of drug
contacts, and have narrow therapeutic indicators. Moreover,
inhibition of these nonselective drugs on the off-target
pathways will damage skeletal muscle (NaV1.4), cardiac tissue
(NaV1.5), and peripheral neurons (NaV1.7, NaV1.8, NaV1.9). It
has been found that selective inhibition of NaV1.6 and NaV1.2
while retaining high selectivity to NaV1.1 is more effective than
currently available ASDs and has fewer side effects on
CNS.139,141 Therefore, isoform-selective or dual-acting
NaV1.6 and NaV1.2 inhibitors may be beneficial to epilepsy
patients.142
In recent years, NaV inhibitors for epilepsy have focused on
the development of subtype-selective inhibitors, mainly
including NaV1.6 and NaV1.2 inhibitors (Figure 4). Focken
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et al. identified indoline scaffold derivative 1 that has moderate
NaV1.6 efficacy and low topological polar surface area (TPSA),
but its metabolic stability and MDR1-mediated efflux are
poor.141 Ring opening of the indoline provided benzylami-
noarylsulfonamide compound 2 with over 17-fold improved
NaV1.6 potency compared to 1. After more systematic and
extensive SAR exploration of this new scaffold, compounds 3, 4
(XPC-6444), and 5 (XPC-6379) were determined as potent
NaV1.6 inhibitors, which also display potent blockage of
NaV1.2 (Figure 4A). These three compounds show excellent
anticonvulsant activity and reduce seizure activity in the
SCN8AN1768D/+ model. They also have good tolerability,
metabolic stability, and low MDR1-mediated efflux. However,
these compounds faced challenges in preclinical toxicology
studies.141 Other reported NaV1.6 or NaV1.2 inhibitors are
shown in Figure 4B. Compound 6 (NBI-921352), a novel
selective NaV1.6 channel inhibitor (IC50 = 0.051 μM), can
effectively prevent electrically induced seizures in
Scn8aN1768D/+ mouse, wild-type mouse, and rat-seizure models.
Compound 6 was tolerated at high multiples of effective
plasma and brain concentrations, which is entering the phase II
clinical trial (NCT04873869) for the treatment of SCN8A-
DEE and adult focal-onset seizures. This compound has
significant promise to be translated into a therapeutic for
individuals with treatment-resistant epilepsy.142 Compounds 7
(Valsartan), 8 (Ciprofloxacin), and 9 (N.N′-diphenethylsulfa-
mide), which can interact with the open conformation of the
Nav1.2 pore but not with P-gp efflux transporter and were
discovered by a sequential virtual screening campaign, are
potentially effective compounds for the treatment of P-gp
mediated resistant epilepsy. These three compounds exhibited
inhibitory effects on the NaV1.2 channel activity and showed
anticonvulsant activity in vivo.143 Compound 10, a mexiletine
analogue, is a highly selective NaV1.2 inhibitor that can inhibit
seizures in a kindled mouse model of refractory epilepsy (6HZ
44 mA).144
4.1.2. Potassium Channel Agonists. The activation of
VGPC-KV7, which includes five members (KV7.1−5), can
reduce the excitability of neurons, which has been proven to be
an effective method for treating epilepsy.145 Retigabine (RTG)
is the first approved neuronal potassium channel agonist for
treating epilepsy. RTG can cause permanent retinal abnormal-
ities, peripheral skin discoloration, bladder dysfunction, and
other side effects. It was withdrawn from markets in 2017.146
Flupirtine, an atypical analgesic drug, was identified as a
KV7.2/3 channel opener.147 It has been proved that Flupirtine
is an extremely effective treatment for neonatal seizures in
rats.148 However, because of rare but severe adverse drug
reactions, namely drug-induced liver injury (DILI), the
European Medical Agency (EMA) recommended the with-
drawal of flupirtine from the market in 2018.149 Studies have
found that retigabine and flupirine, both containing a
triaminoaryl scaffold, can be oxidized to reactive quinone
diimide or azoquinone diimide metabolites in vivo.150
Flupirtine is an active metabolite, such as azoquinone diimide,
that can directly cause cellular damage or form haptens in the
liver, which can trigger toxic autoimmune reaction and
eventually lead to rare but serious liver toxicity.151 Retigabine
active metabolite, such as quinone diimide, can dimerize to
phenazinium structures, thus causing blue discoloration of
various tissue.152
To avoid the formation of quinone or azoquinone diimine
metabolites, improve the drugs photosensitivity, improve
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Figure 5. (A) Chemical structures of novel Kv7 inhibitors. (B) Chemical structures of KNa1.1 inhibitors.
brain/plasma (B/P) concentration ratio, reduce the undesir-
able side effects, and increase potency at specific Kv7 channel
subtypes, novel candidate drugs have been developed (Figure
5A). Compound 11 was obtained by replacing the carbamate
group of retigabine and flupirtine with an inverted amide and
introducing an essential methyl group. Compound 11 showed
six times more potent compared to flupirtine and is devoid of
the potential for azaquinone diimine formation.150 Compound
12 is a potent and photochemically stable neuronal Kv7
channel activator, which displayed a higher B/P distribution
ratio, no photoinduced dimer formation, a longer plasma half-
life in vivo and higher potent and effective anticonvulsant
effects in an acute seizure model in mice.19 Compound 13 (P-
RTG) is an RTG analogue developed by incorporating a
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propargyl group at the N position of the RTG linker. The B/P
concentration ratio of 13 increased to 2.3 (RTG = 0.16). The
antiepileptic activity of 13 was significantly enhanced to a value
2.5 times greater than that of RTG.153 Compound 14 (HN37)
was obtained by deleting the ortho-liable −NH2 group and
installing two adjacent methyl groups to the carbamate motif
of compound 13. Compound 14, with its improved chemical
stability, strong efficacy, and better safety threshold, has strong
activation potency toward neuronal KV7 channels and high
efficacy in vivo. Compound 14 has entered the clinical trial in
China for epilepsy treatment.154 Compounds 15 and 16 are
two RTG conformational restriction analogues obtained by
introducing the N5-alkyl amine indole moiety, which showed
higher potency in activating heteromeric KV7.2/KV7.3 channels
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Figure 6. (A) The optimization process of compound 31. (B) The optimization process of compound 34. (C) The optimization process of
compound 36. (D) Chemical structure of compound 37.

and improved chemical stability.155 Compound 17 selectively
activates the KV7.2/7.3 channel in a dose-dependent manner in
HEK293 cells. The EC50 value of 17 is 100 times stronger, and
its antiepileptic effect is 10 times that of RTG.156
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Treatment options for KCNT1-related diseases are limited,
and conventional drugs are often ineffective. Quinidine,
clofilium, and bepridil have been proposed as treatment
options for seizures and comorbidities.157,158 However, novel
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Figure 7. (A) Chemical structures of GABAAR modulators. (B) Chemical structures of GAT inhibitors.
therapies are urgently required because of their nonspecific,
low potency or side effects.158,159 Several compounds that
specifically inhibit KNa1.1 have been investigated (Figure 5B).
Compound 18 (VU0606170) is a selective KNa1.1 inhibitor
with low micromolar potency screened by a high-throughput
thallium flux assay. Compound 18 can significantly reduce the
firing rate in overexcited and spontaneously firing cortical
neuron cultures.160 Compounds 19−24, obtained by virtual
screening based on chicken KNa1.1 cryo-EM structure, can
inhibit the KNa1.1 channel with low- and submicromolar
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potencies, which are more potent than quinidine. Except for
compound 21 and 24, the other four compounds are effective
in hERG inhibition and cytotoxicity assays. These may provide
a starting point for developing new pharmacophores, and could
become key compounds for further research on this
channel.158 Compound 25, a novel oxadiazole KNa1.1 inhibitor,
can reduce seizures and interictal spikes in a KCNT1-GoF
mouse model.161
4.1.3. Calcium Channels Blockers. TTCCs (CaV3.1,
CaV3.2, and CaV3.3 channels) play an important role in IGE
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in humans and animals.162 Ethosuximide as a small-molecule
blocker of TTCCs is the earliest ASD used to treat absence
epilepsy.163 However, TTCCs are widely distributed in various
tissues and have close homology with other voltage-gated
channels. Therefore, it is challenging to design selective T-type
calcium channel blockers. It is important to break through this
limitation and find more effective compounds.164
Recent research focuses on discoverying and developing
potent, selective, and brain-penetrant TTCC blockers (Figure
6). Bezençon et al.165 identified compound 26 as a moderately
effective TTCC blocker that has certain selectivity over
CaV1.2. Optimization of the phenylacetic acid part and the
N-benzyl substituent on the pyrazole ring of compound 26 led
to compound 27 as a triple point TTCC blocker that showed
excellent efficiency in the WAG/Rij rat epilepsy model. To
search for a good balance between solubility, metabolic
stability, and active efflux, compounds 28 and 29 were
obtained by introducing indolyl and oxalkyl into the para-
position of phenylacetic acid. To find the amino-pyrazole
metabolite that tested negative in the Ames test, moiety 30 was
introduced into the compound. After the final optimization,
compound 31 (ACT-709478) was obtained, which is in phase
2 clinical trial (NCT03239691) (Figure 6A). Remen et al.166
identified dihydropyrazole 32 as a compound with a promising
potency on CaV3.2 and good selectivity for CaV1.2 by high-
throughput FLIPR experiment. Compound 33 was found to
have higher potency toward CaV3.2 and was optimized by
introducing a para-fluoro substituent to the urea moiety of 32.
A 4-pyridinyl group was introduced to position 3 to obtain
compound 34 with acceptable solubility. Compound 34
advanced to in vivo studies and demonstrated efficacy in the
WAG/Rij rat model of generalized nonconvulsive, absence-like
epilepsy (Figure 6B). Siegris et al.167 identified that compound
35 has good activity for CaV3.1, CaV3.2, and CaV3.3 channels
and a good selectivity for CaV1.2 channels but poor
physicochemical and in vitro DMPK properties. Optimization
work led to preparing pyridodiazepine 36 with improved
physicochemical properties, solubility, and metabolic stability,
which showed promising efficacy in the WAG/Rij-rat model
(Figure 6C). Compound 37 (Z944), a potent TTCC
antagonist, can significantly inhibit absence seizures (85−
90%) in the GAERS model and the kindling process in the
amygdala kindling model of TLE (Figure 6D).34,168
4.2. Enhancement of GABA-Mediated Inhibitory
Neurotransmission. GABA is a major inhibitory transmitter
that controls synaptic transmission and neuronal excitability. It
was found that enhancing GABA inhibition can reduce or
inhibit seizures.169 Here, we summarize the small-molecule
compounds that can enhance GABAergic inhibition reported
in recent years, including 10 types of GABAAR modulators, six
types of GAT inhibitors, and six types of GABA-AT inhibitors.
4.2.1. GABAAR Modulators. GABAARs are composed of 19
members of the GABA protein family (α1-6, β1-3, γ1-3, δ, ε, θ,
π, and ρ1-3), which are important targets for CNS drugs,
especially epilepsy.170 Although several ASDs that have been
approved for marketing can act on focal epilepsy through
GABAAR to enhance the inhibitory effects of GABA, it is still
necessary to develop more potent and more specific GABA
ASDs that are effective in drug-resistant patients with focal
epilepsy.171
Figure 7A shows the novel representative of selective
GABAAR modulators developed in recent years. Compound
38 (KRM-II-81) is an α2/3-selective GABAAR modulator and
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is active against electric-shock-induced convulsions in mice,
PTZ-induced convulsions in rats and amygdala-kindled
seizures in rats. It shows a wide therapeutic range for exercise
side effects.172 Compound 39 (PF-06372865/CVL-865) is an
α2/3/5-selective GABAAR modulator and can effectively
inhibit the peak-wave discharge of rats in a GAERS genetic
absence epilepsy rat model, which has entered a phase 2
clinical trial (NCT04244175).173 Compound 40 is a β2/3
subunit-selective GABAAR modulator screened by pharmaco-
phore model, which has the strongest regulatory ability on
GABA-induced chloride current and stronger protective effect
on PTZ-induced seizures. It can promote the phased and
persistent GABAergic inhibition of hippocampal neurons.174
Compound 41 is an α-asaronol esters analogue that exhibits
good modulatory activity on human α1β2γ2-GABAAR and can
significantly attenuate neuropathic pain in the mice formalin
model. Compound 41 was a promising candidate for treating
refractory epilepsy such as Dravet syndrome. 175 The
benzodiazepine site (BZ-S) on the GABAA receptor is an
important active site of ASDs. Benzenediazepines (BZDs)
enhance the role of the neurotransmitter GABA mainly
through agonists binding to the BZD pocket, which play an
important role in treating epilepsy.176 However, the non-
selective combination of these drugs leads to serious side
effects, including dependence, unnecessary sedation, and
amnesia.177 Different effective antiepileptic compounds 42−
47 (Figure 7A) with a BZD scaffold have been proposed to
target GABAARs through computer-aided drug design.40,178
4.2.2. GAT inhibitors. GATs belong to the solute carrier 6
gene family A (SCL-6). There are four different subtypes in
mice: mGAT1, mGAT2, mGAT3, and mGAT4, which
correspond to hGAT-1, hBGT-1, hGAT-2, and hGAT-3 in
humans, respectively.179 mGAT1 is the most prevalent GAT,
which is almost exclusively located in the CNS. It was
identified as a major pharmacological target.180 Tiagabine was
the first highly effective and selective GAT1 inhibitor that was
approved by the U.S. FDA for treating partial epileptic seizures.
However, the half-life of tiagabine is very short and additionally
may cause dizziness, weakness, trembling, tension, diarrhea,
depression, and other side effects.181
Figure 7B shows GAT inhibitors identified in recent years.
Compound 48 (DDPM-2571), a tetrahydronicotinic acid
derivative, is a novel, highly potent and in vivo active GAT1
inhibitor with anticonvulsant, anxiolytic, antidepressant, and
antinociceptive properties.182 Compounds 49−51 with high
antiseizure activity, low neurotoxicity, and good safety profiles
that have been evaluated by epilepsy animal models, whose
potential target was speculated as GAT1 by molecular
docking.183 Compound 52 (a butylamine derivative) is a
nonselective GAT inhibitor with a slight preference toward
mGAT4 (pIC50: 5.02 ± 0.11) and showed predominant
anticonvulsant activity and antinociception in the formalin
model of tonic pain.41 In recent years, studies have found that
BGT1 inhibitors also have antiseizure effects.184 Compound
53 (SBV2-114), derived from tiagabine, is a BGT1 inhibitor
with >13-fold selectivity for BGT1 over the other GAT
subtypes.185 SBV2-114 was found to have an elusive biphasic
inhibition profile with two IC50 values (4.7 and 556 μM)
determined by a cell-based [3H] GABA uptake assay. SBV2-
114 shows antiseizure effects in an audiogenic-induced seizure
model. This compound may ultimately contribute to our
understanding of GAT transport mechanisms and become a
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Figure 8. (A) Chemical structures of GABA-AT inhibitors. (B) Chemical structures of AMPAR and NMDAR antagonists.
lead compound for designing of more selective BGT1
inhibitors.186
4.2.3. GABA-AT Inhibitors. GABA-AT is a pyridoxal-5-
phosphate (PLP) dependent enzyme that can degrade GABA
into succinic acid semialdehyde.187 GABA-AT is a recognized
target for ASDs, and GABA-AT selective inhibition plays an
antiseizure role by increasing the concentration of GABA in
the brain.188 Vigabatrin, a known GABA-AT inhibitor, was
approved by FDA in 2009 as an adjunctive treatment for
refractory partial seizures.189 However, long-term use of
vigabatrin may cause permanent visual damage.190
To increase the potency and eliminate retinal toxicity,
several vigabatrin analogues have been designed (Figure 8A).
Compound 54 (CPP-115) is a novel GABA-AT inhibitor that
is 187 times more potent in inactivating GABA-AT than
vigabatrin, markedly reduced seizures with no evidence of
retinal dysfunction in a patient with refractory infantile
spasms.191 Compound 55 (OV329) is modified from 54 and
appears superior in both anticonvulsant potency and efficacy to
vigabatrin, which shows pronounced anticonvulsant effects in
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the pentylenetetrazole seizure threshold test and in amygdala-
kindled rats.192 It has been reported that OV329 is well
tolerated for assessed ocular end points.193 Compounds 56 and
57, two 5,6-dihydropyrimidine-2(1H)-thione derivatives, were
found active in two epilepsy models (MES and scPTZ). They
showed in vitro GABA-AT inhibitory potency of 18.42 μM and
19.23 μM, respectively.194 Compound 58 is a pyrimidine-
carbothioamide derivative that can effectively suppress seizure
in different animal models with median doses of 15.6 mg/kg
(MES ED50), 278.4 mg/kg (scPTZ ED50), and 534.4 mg/kg
(TD50), with no sign of neurotoxicity. In vitro, the GABA-AT
enzyme activity assay of 58 showed inhibitory potency (IC50)
of 12.23 μM.195 Compounds 59 is a parabanic acid derivative,
exhibiting the most potent activity against electric stimuli-
induced seizures and a protective index greater than 36.5.
Additionally, a molecular docking study of this compound
indicated good interaction on the active site of GABA-AT.196
4.3. Attenuation of Glutamate-Mediated Excitatory
Neurotransmission. Glutamate-mediated neuronal over-
excitation plays a critical role in inducing seizures. NMDAR
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Figure 9. Chemical structures of CA inhibitors.
or AMPAR antagonists have been shown to inhibit seizures in
animal models, indicating their potential role in the develop-
ment of ASDs.
4.3.1. AMPAR Antagonists. AMPAR is a transmembrane
complex composed of four subunits (GluA1−GluA4), which is
a therapeutic target for epilepsy treatment.197 Perampanel is
the only clinically approved noncompetitive AMPAR antago-
nist. It acts as an adjunctive treatment for partial-onset and
generalized tonic-clonic seizures over 12 years of age.115
However, CNS-related side effects such as dizziness, sedation,
and falls have been reported at treatment doses.198 Although
AMPARs are widely distributed throughout the brain, their
activity can be regulated by transmembrane AMPAR
regulatory proteins (TARPs). TARPs are classified into type
I (γ-2, γ-3, γ-4, γ-8) and type II (γ-5, γ-7) by sequence
homology. Among them, TARP γ-2 is highly expressed within
the cerebellum, which is involved in motor coordination, while
TARP γ-8 is highly expressed in the hippocampus.199 Recent
studies have found that selective TARP γ-8-dependent
AMPAR antagonist is expected to become novel effective
ASDs without motor impairment.200
Representative TARP γ-8-dependent AMPAR antagonists
are shown in Figure 8B. Compound 60 is an aminothiazole
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derivative, with high efficacy in vitro, low drug clearance, and
AMPAR/TARP γ-8 selectivity, which displayed potent
antiseizure efficacy in rats against PTZ-induced convulsions
without motor side effects.201 Compound 61 (JNJ-55511118)
is highly potent and selective for AMPA receptors containing
TARP γ-8. It had good pharmacokinetic characteristics and
high receptor occupancy after oral administration. Although
hepatotoxicity in rats prevented developing compound 61, this
compound showed a strong dose-dependent inhibition of
neurotransmission in the hippocampus and a strong anti-
convulsant effect without causing sedation or motor impair-
ment.202 Replacement of the benzimidazolone core in 61 with
an oxindole scaffold and introduction of a methyl group in the
7-position leads to the identification of compound 62, which
demonstrated robust target engagement in the hippocampus
(ED50 = 0.6 mg/kg, plasma EC50 = 9 ng/mL).This compound
exhibited higher potency and lower efficacious plasma
concentration, and can reduce the formation of a reactive
metabolite.203 Compound 63 (JNJ- 61432059) is a TARP γ-8
selective AMPAR modulator, which showed time- and dose-
dependent receptor occupation in mouse hippocampus after
oral administration and strong seizure protection in corneal
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Figure 10. (A) Chemical structures of mTOR inhibitors. (B) Co-crystal structure of p110a and compound 80 complex. Compound 80 was best
accommodated with the methyl group in one of the two hydrophobic interfaces formed by side chains of Tyr836, Ile848, Ile932 or Trp780, Ile800,
and Val850 (PDB code 6OAC). (C) Chemical structures of a COX-2 inhibitor, H3R antagonists, and an sEH inhibitor.

kindling and PTZ anticonvulsant models without damaging
motor function.46
4.3.2. NMDAR Antagonist. NMDARs are related to the
pathogenesis of epilepsy and are widely expressed in the
cerebral cortex and hippocampus.204 NMDAR antagonists,
including topiramate (TPM) and zolesamide, can inhibit
glutamate release. Ketamine, another NMDAR antagonist, has
no stable effect when used alone in the status epilepticus
animal model, but it has synergistic effect when used in
combination with other drugs.205 Although these NMDAR
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antagonists can control epilepsy, there is no sufficient evidence
to prove their efficacy and safety.116,206
There is little research on NMDAR antagonists in recent
years. Compound 64 (DDBM) (Figure 8B) is a novel indolyl
derivative that has robust anticonvulsive activity in a rat
electroconvulsive shock (ECS) model of epilepsy. It may
antagonize the binding sites of the NMDA receptor as
indicated by computational docking.207
4.4. New Target Compounds. With an in-depth under-
standing of the pathogenesis of epilepsy, researchers have
found new targets to develop novel antiepileptic compounds,
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such as mTOR inhibitors, CA inhibitors, cannabinol,
adenosine inhibitors, and anti-inflammatory drugs.
4.4.1. CA Inhibitors. Carbonic anhydrase (CA) is a
ubiquitous zinc metalloproteinase, which has 15 different
subtypes in human (hCA I−hCA XV).208 CAs can catalyze the
reversible hydration of carbon dioxide into bicarbonate
(HCO3−) and proton (H+). The CO2/HCO3 buffer system
mainly maintains the balance of pH in the brain and plays a
key role in the initiation and progression of epilepsy.209 CAs
can influence the function of transmembrane proteins
implicated in neuronal signaling, such as NMDARs and
GABAARs, which may affect epileptic activity.210 Some
sulfonamide CA inhibitors, including acetazolamide (AAZ),
topiramate (TPM), metazolamide (MZA), and zonisamide
(ZNS), have good anticonvulsant activity and are still used in
the clinic for treating various forms of seizures.211 However, it
is clinically demonstrated that some CA inhibitors are not
effective when used alone or in long-term epilepsy therapy and
have serious side effects which are related to the inhibition of
the off-target CA isomers.212 Therefore, developing new CA
inhibitors with long-lasting efficacy and minor side effects is
required.
In the past years, one strategy to develop compounds
displaying effective anticonvulsant activity is to target CA II
and CA VII isoforms in the brain.213 The benzenesulfonamide
(ZBG) scaffold (Ar-SO2NH2) has emerged as a pharmacody-
namic head for designing effective and isomer-selective CA
inhibitors.214 The pharmacophore frame of CA inhibitors
consists of a head region (ZBG), a linker/spacer such as
carbamide, urea, thiourea, hydrazide, and amide, and a tail
region with alkyl/aryl/heteroaryl/sugar scaffolds (Figure 9).132
For compounds 65−67, the head ZBG is connected with a
piperazine tail through ethyl urea/acetamide. They have the
strongest inhibitory effect on hCA II and hCA VII and display
effective seizure protection against MES and scPTZ-induced
seizures. They showed minor toxicity in subacute toxicity
studies.215 For compounds 68−70, the BZG head is connected
to the piperazine tail through the benzylidene hydrazine/
benzylidene hydrazine carbonyl. Compounds 68 and 69 have a
good inhibitory effect on hCA II and hCA VII. Compound 70
only has an inhibitory effect on hCA VII. These three potent
inhibitors significantly inhibited seizures induced by MES and
scPTZ in mice. Compound 70 has the strongest anticonvulsant
effect, without obvious neurotoxicity and hepatorenal toxicity,
which can effectively eliminate epilepsy in a rat model.216 For
compounds 71−73, the BZG head is connected with the
piperazine tail through N-methylacetamide and N-methylpro-
pionamide, which are the most effective inhibitors of hCA II
and hCA VII. The three derivatives show effective anti-
convulsant activity against epilepsy induced by MES and
scPTZ. Among them, compound 71 has the strongest
anticonvulsant effect and low therapeutic dosage (30 mg/
kg). After oral administration, it can eliminate the MES
stimulation of male Wistar rats without showing neuro-
toxicity.217 Compounds 74 and 75 were synthesized by
substituting acetamide for propionamide linker and piperazine
for aniline/benzothiazole tail based on 73. These two
compounds are the most effective inhibitors of hCA II and
hCA VII, which have long-term effects on seizures caused by
MES. After 6 h of administration, they show 75% and 25%
protective effects respectively, without neurotoxicity.218
4.4.2. mTOR Inhibitors. mTOR is a highly conserved
serine/threonine kinase that belongs to the phosphatidylino-
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sitol 3-kinase (PI3K) related kinase protein family.219 The
earliest mTOR inhibitors are mainly rapamycin and its
derivatives, whose mechanism of action is mainly to inhibit
mTOR activity by binding with other intracellular receptors
FKBP12. Tuberous sclerosis complex (TSC) is a genetic
epilepsy that involves mutations in the TSC1 and/or TSC2
genes, which lead to reduced inhibition of mTOR or abnormal
activation of mTOR.220 In a TSC animal model, rapamycin
can significantly prevent the occurrence and development of
epilepsy and improve its survival rate. Everolimus is a
rapamycin analogue that can effectively reduce the frequency
of seizures in TSC patients and the size of TSC-related solid
tumors. It was approved for market in 2018.221 However, the
inhibition of rapamycin and its analogues on TORC1 is not
effective for all TSC patients because their drug resistance and
adverse side effects will lead to treatment termination and dose
reduction.222 Therefore, finding mTOR inhibitors with optimal
brain permeability is of paramount importance for CNS
disease treatment.
Beaufils et al.223 reported a pan-PI3K/mTOR inhibitor 76
(PQR309) (Figure 10A), which has good brain penetrability
and oral bioavailability. It has entered clinical phase II for
treating solid tumors and lymphoma. Rageot et al.224
optimized PQR309 and developed compound 77 (PQR620),
which is an effective, selective, and a brain-penetrable
mTORC1/2 kinase inhibitor. It has a strong selective
inhibitory effect on mTOR kinase (Ki mTOR: 0.33 nM). It
reduces seizures in a TSC mouse model and has antitumor
effects in vitro and in vivo. Ethylene-bridged morpholine in
compound 77 has been identified as the main metabolic site of
human liver microsome cells.225 Therefore, Borsari et al.
optimized 77 to obtain compound 78 (PQR626) with higher
metabolic stability. Compared with 77, the stability of 78 in
human hepatocytes has been improved by 50%. Compound 78
has excellent brain penetration ability and shows effectiveness
in the TSC mouse model.133 Rageot et al.226 explored the
morpholine part of PQR309 for compound 79, which contains
a 1(S)-3-methylmorpholine (M2) group, and they found the
strongest effect on PI3K and mTOR. Its affinity increased by
two times compared with PQR309. After optimizing the
trifluoromethyl group, they obtained compound 80
(PQR530), which is a drug-like inhibitor of PI3K/mTOR
kinase that has subnanomolar Kd values of 0.84 and 0.33 nM
for PI3K and mTOR kinase, respectively. Compound 80 can
quickly enter the brain, reaching a brain-to-plasma ratio of
∼1.6. In addition, it significantly reduced the phosphorylation
level of S6 ribosomal protein in the hippocampus of normal
and epileptic mice, showing an effective inhibition of mTOR.
Compound 80 significantly increased the seizure threshold at a
tolerable dose (Figure 10A,B).
4.4.3. COX-2 Inhibitors. Cyclooxygenase-2 (COX-2) is an
enzyme that synthesizes proinflammatory prostaglandins, is a
potential therapeutic target for epilepsy.227 Currently, the
research of COX-2 inhibitors as ASDs is still in the preclinical
stage. Some drugs, such as aspirin and rofecoxib, have been
evaluated to have antiepileptic effects in acute epilepsy and
chemical convulsions or electrical models of epilepsy.228
However, these compounds have low selectivity to COX-2,
with poor pharmacokinetics and severe hepatotoxicity after
long-time use.229 Therefore, COX-2 inhibitors must be
researched to have small toxicity, higher potency, and
increased selectivity.
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Figure 11. (A) Design strategy and general structure of hybrid compounds. (B) Chemical structure of other multitargeted compounds.
Compound 81 (MLT-1) (Figure 10C) is a methyl sulfonyl
phenyl derivative, showed good protection against scPTZ-
induced acute seizures and 67% long-term epilepsy protection
after administration, and successfully improved the cognitive
impairment of PTZ kindled rats. The molecular simulation
showed that MTL has good interaction with the COX-2 active
site. Therefore, MLT-1 was determined an effective COX-2
inhibitor, which also shows excellent anticonvulsant and
cognitive enhancement potential without any significant
toxicity.230
4.4.4. H3R Antagonists. Histamine is an important neuro-
transmitter that exerts biological activity through four different
G-protein coupled receptors (H1−H4).231 H3 receptors
(H3Rs) are abundantly expressed in the central nervous
system and can also act as foreign receptors to regulate the
release of other neurotransmitters, such as acetylcholine,
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glutamate, and aminobutyric acid in different regions of the
brain.232 Therefore, H3R is considered a pharmacological
target for developing central nervous system diseases, including
epilepsy and cognitive impairment.233 Currently, a series of
nonimidazole H3R antagonists with anticonvulsant activity
have been developed, including compounds 82−85 (Figure
10C) that show dose-dependent anticonvulsant and cognitive
promoting properties in MES-induced seizure model.234
4.4.5. sEH Inhibitors. In recent years, the roles of the
arachidonic acid (AA) metabolic pathway in inflammation
have been widely studied. In the brain parenchyma, free AA is
metabolized into different types of epoxyeicosatrienoid acids
(EETs) by cytochrome P450 (CYP450) epoxygenases, which
are considered antineuroinflammatory or antiapoptotic mole-
cules.235 However, EETs are easily hydrolyzed by soluble
epoxide hydrolase (sEH) to form the less active form of
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dihydroxyeicosatrienoic acids.236 It has been suggested that
inhibition of sEH can increase the level of EETs and improve
the neuronal damage caused by cerebral ischemia.237 In a
murine model of acute tetramethylenedisulfotetramine
(TETS) intoxication, postexposure administration of diazepam
combined with an sEH inhibitor stops seizures and modulates
neuroinflammation.238 Therefore, sEH is a potential target for
the treatment of epilepsy. 86 (TPPU), a type of sEH inhibitor
that can cross the blood−brain barrier, could alleviate
spontaneous recurrent seizures (SRS) and epilepsy-associated
depressive behaviors in the lithium chloride (LiCl)-pilocar-
pine-induced poststatus epilepticus (SE) rat model.239
4.5. Multitargeted Compounds. Multifunctional (or
multitargeted) ASDs, such as valproic acid (VPA), are the
most commonly used and effective compounds for treating
different types of epilepsy.240 The combination of different
molecular mechanisms is often more beneficial for DRE.241
Multitargeted ASDs (involving synergistic or additive mecha-
nisms) may provide a wider activity spectrum and a better
therapeutic window (Figure 11).
A series of hybrid molecules with a pyrrolidine-2,5-dione
core was developed by combining the active fragments of
ethosuximide, levetiracetam, and lacosamide with the frame-
work combination approach. Compounds 87 and 88 showed
high anticonvulsant activity in MES, scPTZ, and 6 Hz seizure
models. Compound 87 had higher protection and safety, and
compound 88 could effectively reduce pain responses in
formalin-induced tonic pain, capsaicin-induced neurogenic
pain, and oxaliplatin-induced neuropathic pain in mice.242 A
new hybrid molecule 89 (KA-104) was obtained by integrating
active moieties of compound 87, BCTC (a TRPV1
antagonist), and lacosamide, which showed the most potent
anticonvulsant activity and efficacy in the formalin-induced
tonic pain.243 To improve the water solubility of the above
compounds, compound 90 was obtained by introducing an
amino group into the pyrroline-2,5-dione ring. Compound 90
had good anticonvulsant and antineurogenic pain activity.
Additionally, compound 90 has good in vitro ADME Tox
characteristics (high metabolic stability, weak influence on
CYPs, no neurotoxicity) and in vivo pharmacokinetics
characteristics.244 Compounds 91 and 92 were obtained by
combining the structural fragment of TRPV1 antagonist with
89 (KA-104), which showed robust in vivo antiseizure activity
in the MES test and 6 Hz seizure model (using both 32 and 44
mA current intensities) and were effective in the ivPTZ seizure
threshold.245 The mechanism of compounds 89−92 may be
due to the inhibition of peripheral and central sodium calcium
currents and the antagonism of the TRPV1 receptor observed
in vitro. In addition, compounds 93−98 with the pyrrolidine-
2,5-dione core also have broad-spectrum antiepileptic activity
developed by combining different drug fragments. In vitro
binding studies showed that the most reasonable mechanism of
these compounds was to affect the voltage-sensitive sodium
channel and L-type calcium channel of neurons.246 Com-
pounds 99 and 100, two isatin arylhydrazone analogues, have
strong anticonvulsant activity and show 100% protective effect
at a dose of 5 mg/kg. Molecular docking studies show that the
binding of VGSCs and GABA-A receptors is the most likely
mechanism of these two compounds.247 Compound 101
(SKA-19), a compound that can activate KCa2 channel and
block NaV channel, has oral bioavailability and shows activity
in a wide range of rodent seizure models.248
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5. CONCLUSIONS AND PROSPECTS
Epilepsy is a common neurological disease that affects about
65 million people worldwide. Nowadays, ASDs are the
mainstay treatment for epilepsy. More than 30 ASDs have
been approved for clinical use. Unfortunately, about 20−40%
of patients do not respond to these ASDs, resulting in DRE. As
the mechanism of epilepsy pathogenesis and drug-resistance
continue to be investigated, ASDs with novel mechanisms of
action, higher efficacy, and reduced side effects are in high
demand, especially for patients with treatment-resistant
epilepsy or treatment-refractory seizures. We elaborated on
the pathogenesis and clinical research progress of epilepsy and
summarized 79 kinds of new antiepileptic small molecules.
These molecules include 27 ion channel modulators, 22 GABA
inhibitors, five glutamate-mediated neuronal excitation modu-
lators, 11 CA inhibitors, three mTOR signal pathway blockers,
one COX-2 inhibitor, four H3R antagonists, one sEH inhibitor,
and 15 small antiepileptic molecules with multiple targets.
These compounds offer great opportunities for the develop-
ment of more promising ASDs.
Nowadays, the marketed ASDs are based on ionic
mechanisms, which directly or indirectly act on sodium,
potassium, and calcium ion channels or GABAAR, AMPAR,
and NMDAR. The specificity of these ASDs is not strong, and
many are effective against multiple diseases. More targeted and
specific drugs for epilepsy need to be developed. In recent
years, small-molecule compounds related to ion channels with
potential antiepileptic effects have also made great progress.
VGSCs are mainly focused on developing selective inhibitors.
Compared with traditional nonselective inhibitors, new
compounds can reduce the adverse reactions caused by off-
target effects, thus improving safety.142 RTG is the only ASD
that acts on VGPCs and was withdrawn from the market due
to serious side effects. Therefore, in recent years, researchers
optimized and modified the chemical structure of RTG to
improve the chemical structure, stability, and potency. Among
them, XEN1101 (1OP-2198) has been used in clinical phase 2
for treating focal epilepsy (NCT03468725).249 HN37 has
completed a clinical phase 1a study (CTR20201676) in China,
with good safety and metabolic characteristics.250 Small-
molecule compounds targeting VGCCs have made a great
breakthrough in treating absence epilepsy, such as ACT-
709478, which has entered phase 2 clinical trials
(NCT03239691).251 Small-molecule compounds targeting
GABAAR have also turned to developing selective inhibitors
to reduce their side effects, which has made good progress in
treating refractory epilepsy, such as DS and absence epilepsy.
PF-06372865/CVL-865 has entered the clinical phase 2 trial
(NCT04244175).38 Selective TARP γ-8-dependent AMPAR
antagonist (TDAA) has become the research direction in this
field, and many small molecules have been developed.
Compared with traditional TARP-independent AMPAR
antagonists, these new TDAA compounds are believed to
provide an increased dose range and better efficacy in patients.
With the in-depth study of the pathogenesis of epilepsy,
nonionic targets have also attracted wide attention, such as CA,
mTOR, inflammation-related protein (COX-2/IL-1β/
HMGB1), 5-HT, and adenosine kinase. Nowadays, only a
few drugs targeting these targets, such as everolimus,
cannabinol, fenfluramine, and anabolin, have achieved clinical
transformation. There are still a large number of nonionic
small antiepileptic compounds in the preclinical development
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stage, which may be a future direction for developing new
ASDs. Researchers have spent a lot of effort designing a variety
of effective and isomer-selective CA inhibitors with benzene-
sulfonamide as the head, which may represent a new promising
treatment strategy. mTOR inhibitor everolimus has been
marketed to treat patients with TSC epilepsy, but its long-term
use is limited by immunosuppression, poor brain penetration,
and feedback circulation induction. Therefore, three novel dual
P13K/mTOR inhibitors with good brain permeability have
been developed in recent years, which may overcome the
shortcomings of rap therapy for epilepsy and mTOR diseases
directly related to mTOR signal cascade mutations. Inflam-
mation is closely related to epilepsy, and a variety of pro-
inflammatory factors have also become targets for the
development of ASDs. There are still many nonionic
antiepileptic mechanisms that have not been clinically
transformed, and it is believed that they will become a new
direction of clinical research and development in the future.
In recent years, the development of ASDs has made great
progress, but epilepsy is a very complex disease. Present ASDs
mainly control the symptoms of seizures but do not aim at the
cause of treatment. In the future, drug research on epilepsy
treatment is anticipated to be more in-depth from the
pathogenesis of epilepsy, revealing molecular targets for
epilepsy for personalized precise treatment, including repur-
posed drugs,252 new small molecules, and other treatments
based on innovative technologies, such as antisense oligonu-
cleotides and gene therapy.9,253 More and more researchers
also treat the occurrence of epilepsy and other manifestations
of the disease from the perspective of epilepsy prevention.
These studies are expected to break through the current
dilemma of epilepsy treatment so that drug treatment is no
longer just to controlling seizure symptoms but also to address
the pathogenesis of epilepsy and fundamentally solve the
outcome of epilepsy treatment.
■ AUTHOR INFORMATION
Corresponding Author
Lei Chen − Department of Neurology, Joint Research
Institution of Altitude Health, State Key Laboratory of
Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital, Sichuan
University, Chengdu 610041 Sichuan, China;
Email: leilei_25@126.com
Authors
Tingting Hu − Department of Neurology, Joint Research
Institution of Altitude Health, State Key Laboratory of
Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital, Sichuan
University, Chengdu 610041 Sichuan, China; orcid.org/
0000-0002-5323-0702
Jifa Zhang − Department of Neurology, Joint Research
Institution of Altitude Health, State Key Laboratory of
Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital and Precision
Medicine Key Laboratory of Sichuan Province & Precision
Medicine Research Center, West China Hospital, Sichuan
University, Chengdu 610041 Sichuan, China; orcid.org/
0000-0001-8618-9200
Jiaxing Wang − Department of Pharmaceutical Sciences,
College of Pharmacy, University of Tennessee Health Science
Center, Memphis 38163 Tennessee, United States
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pubs.acs.org/jmc Perspective
Leihao Sha − Department of Neurology, Joint Research
Institution of Altitude Health, State Key Laboratory of
Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital, Sichuan
University, Chengdu 610041 Sichuan, China
Yilin Xia − Department of Neurology, Joint Research
Institution of Altitude Health, State Key Laboratory of
Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital, Sichuan
University, Chengdu 610041 Sichuan, China
Tyler C. Ortyl − Department of Pharmaceutical Sciences,
College of Pharmacy, University of Tennessee Health Science
Center, Memphis 38163 Tennessee, United States
Xiaohe Tian − Department of Neurology, Joint Research
Institution of Altitude Health, State Key Laboratory of
Biotherapy and Cancer Center, National Clinical Research
Center for Geriatrics, West China Hospital, Sichuan
University, Chengdu 610041 Sichuan, China; orcid.org/
0000-0002-2294-3945
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jmedchem.2c01975
Author Contributions
T.H., J.Z., and J.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
Biographies
Tingting Hu received her Ph.D. degree from Sichuan University in
2019 and is currently a postdoctoral fellow at the State Key
Laboratory of Biotherapy and Cancer Center, West China Hospital,
and Collaborative Innovation Center of Biotherapy, Sichuan
University. Her research interest focuses on drug design and discovery
based on structure biology and studying the antineurotic diseases
mechanism of small-molecule compounds.
Jifa Zhang received his Ph.D. degree from Southwest Jiaotong
University in 2018 and is currently a postdoctoral fellow at the State
Key Laboratory of Biotherapy and Cancer Center, West China
Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan
University. His research interests focus on the discovery, optimization
and studying the molecular mechanism of candidate small-molecule
compounds with antitumor activity.
Jiaxing Wang received his B.S. degree and M.S. degrees from Peking
University Health Science Center (Beijing, China). He then joined
Dr. Wei Li’s lab at the University of Tennessee Health Science Center
(UTHSC; Memphis, TN, United States) in 2019. His current
research focuses on biological evaluation of TRPC3 antagonists
developed by the lab.
Leihao Sha is currently a M.D. candidate at the Department of
Neurology, West China Hospital, Sichuan University. His research
interests focus on safer small-molecule drug therapy in neuro-
degenerative diseases for women of childbearing age, especially
epilepsy.
Yilin Xia is currently a M.D. candidate at the Department of
Neurology, West China Hospital, Sichuan University. Her research
interests focus on genetic mechanism and small-molecule therapy in
epilepsy and comorbidities including polycystic ovary syndrome.
Tyler C. Ortyl received his B.S. degree from The University of
Toledo (Toledo, OH, United States). He then joined Dr. Francesca-
Fang Liao’s lab as a research assistant at the University of Tennessee
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J. Med. Chem. 2023, 66, 4434−4467
Journal of Medicinal Chemistry
Health Science Center (UTHSC; Memphis, TN, United States) in
2021.
Xiaohe Tian obtained his M.S. degree under cosupervision of Prof.
Jim A. Thomas and Prof. Giuseppe Battaglia from the department of
Engineering Materials. He continued a Ph.D. degree with Prof. G.
Battaglia at University of Sheffield at the department of Biomedical
Science until 2013. This was followed by two years postdoctoral
program at University College London, department of Chemistry
(2013−2015). He now working in Sichuan University, West China
Hospital as a full professor. His research has concentrated on
functional nanosystem for treating central nervous system disease, and
functional bioimaging including super-resolution imaging and electron
microscopic imaging.
Lei Chen received her Ph.D. degree from Sichuan University and is
now a neurologist and professor in the Neurology department of West
China Hospital, Sichuan University. Her research interests focus on
the etiology, pathogenesis, diagnosis, and small molecule drug therapy
of neurodegenerative diseases, especially epilepsy. Her current
research focuses on the molecular mechanism and optimization of
small-molecule compounds as a therapy to epilepsy, role of noncoding
RNA in refractory epilepsy, brain imaging studies of epilepsy and
metabolic mechanisms of epilepsy.
■ ACKNOWLEDGMENTS
This work was supported by grants from National Natural
Science Foundation of China (82271500, 81903502), Key
R&D Plan of Sichuan Province (23ZDYF2200), and Natural
Science Foundation of Sichuan Province (2022NSFSC1365).
■ ABBREVIATIONS USED
ASDs, antiseizure drugs; AMPAR, α-amino-3-hydroxy-5-
methyl-4-isoxazole propionic acid receptor; AAZ, acetazola-
mide; AA, arachidonic acid; BBB, blood−brain barrier; brain/
plasma, B/P; COX2, cyclooxygenases-2; CA, carbonic
anhydrase; CYP450, cytochrome P450; DRE, drug-resistant
epilepsy; DS, Dravet syndrome; DEE, developmental and
epileptic encephalopathy; EIEE, early infantile epileptic
encephalopathy; ERS, endoplasmic reticulum stress; EET,
epoxyeicosatrienoid acid; FS, febrile seizures; FDA, Food and
Drug Administration; FAAH, fatty acid amide hydrolase;
GEFS+, generalized epilepsy with febrile seizures plus; GOF,
gain-of-function; GABA, γ-aminobutyric acid; GAD, glutamic
acid decarboxylase; GATs, GABA transporters; GABA-AT,
GABA aminotransferase; GABAR, GABA receptors; HMGB1,
high-mobility group box 1; H3Rs, H3 receptors; ILAE,
International League Against Epilepsy; IGE, idiopathic
generalized epilepsy; iGluR, ionotropic glutamate receptors;
IL-1β, interleukin-1β; iNOS, inducible nitric oxide synthase;
KAR, kainate receptor; LTP, long-term potentiation; LiCl,
lithium chloride; mGluR, metabotropic glutamate receptor;
MFS, mossy fiber sprouting; mTOR, mechanistic target of
rapamycin; MES, maximal electroshock; NPY, neuropeptide Y;
MZA, methazolamide; NCAM, neural cell adhesion molecule;
NMDAR, N-methyl-D-aspartate receptor; NOX, NADPH
oxidase; NF-κB, nuclear factor-Κ B; OS, oxidative stress;
PGE2, prostaglandin-E2; PAMs, positive allosteric modulators;
PLP, pyridoxal-5-phosphate; PI3K, phosphatidylinositol 3-
kinase; ROS, reactive oxygen species; RNS, reactive nitrogen
species; RTG, retigabine; SRS, spontaneous recurrent seizures;
scPTZ, subcutaneous pentylenetetrazol; SCL-6, solute carrier 6
gene family; sEH, soluble epoxide hydrolase; SE, status
epilepticus; TTCC, T-type calcium channel; TNF-α, tumor
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necrosis factor α; TNF-β, transforming growth factor β; TLE,
temporal lobe epilepsy; TARPs, transmembrane AMPAR
regulatory proteins; TPM, topiramate; TSC, tuberous sclerosis
complex; TETS, tetramethylenedisulfotetramine; VGSCs,
voltage-gated sodium channels; VGPCs, voltage-gated potas-
sium channels; VGCCs, voltage-gated calcium channels; ZNS,
zonisamide; ZBG, benzene sulfonamide
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