Drug Receptors: Digviaya Lecturer School of Medical & Allied Sciences GD Goenka University

DRUG
RECEPTORS
Digviaya
Lecturer
School of Medical & Allied Sciences
GD Goenka University
1. Introduction
2. History
3. Drug-Receptor Interactions
4. Classification
5. Transducer mechanisms
6. Regulation of receptors
7. Function of receptors
8. Recent advances
9. Summary
10. References
Introduction
•The term drug receptor or drug target denotes the cellular macromolecule or macromolecular
complex with which the drug interacts to elicit a cellular response, i.e., a change in cell
function.
• These are the sensing elements in the system of chemical communications that coordinates the
function of all the different cells in the body.
GOODMAN, GILMAN, L.BRUTON: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS; 12TH EDITION, NEW YORK: MCGRAW HILL
MEDICAL; 2011.
HISTOR
Y
1. The birth of the receptor concept was the outcome of circumstances in the
lives of its two founding fathers, the physiologist John Newport Langley
(1852–1925) and the immunologist and bacteriologist Paul Ehrlich
(1854– 1915).
2. John N. Langley is known as one of the fathers of the chemical receptor

theory, and gave the origin of the concept of "receptive substance“ in
1878.
3. P. Ehrlich designated the term ‘Receptor’ in 1900.
K.D TRIPATHI: ESSENTIALS OF MEDICAL PHARMACOLOGY; 7TH EDITION. NEW DELHI: JAYPEE BROTHERS; 2013.
Theories Proposed
Receptor occupancy theory:
 Clark (1937) propounded a theory of drug action based on occupation of receptors by specific
drugs.
The interaction between the two molecular species, viz. drug (D ) and receptor (R) to be
governed by the law of mass action, and the effect (E) to be a direct function of the drug-
receptor complex (DR) formed.
Contd….
Two – state receptor theory:
 It was first described by Black and Leff in 1983 as an alternative model of receptor activation.
 It proposes that ligand binding results in a change in receptor state from an inactive to an
active state based on the receptor's conformation.
 A receptor in its active state will ultimately elicit its biological response.
Contd
….
 It is model proposed for explaining the action of
agonists, antagonists, partial agonists and inverse
agonists.
 The receptor is believed to exist in two

interchangeable states: Ra (active) and Ri (inactive)
which are in equilibrium.
 In the case of majority of receptors, the Ri state is

favoured at equilibrium
Drug-Receptor Interactions
The drug receptor interaction is characterized by (1) binding of drug to receptor and
(2) generation of a response in a biological system.
Affinity: The ability of the drug to bind with the receptor and form D-R complex.
Intrinsic activity (IA) or efficacy: The capacity of the drug to induce a functional
change in the
receptor after binding.
Contd….
Based on Affinity and Intrinsic Activity, the drug can be labelled as follows:
 Agonist: An agent which activates a receptor to produce an effect similar to that of the
physiological signal molecule. Agonists have both affinity and maximal intrinsic activity
(IA
= 1). e.g. adrenaline, acetylcholine, histamine, morphine.
 Antagonist: An agent which prevents the action of an agonist on a receptor or the

subsequent response, but does not have any effect of its own. Competitive antagonists have
affinity but no intrinsic activity (IA = 0), e.g. propranolol, atropine, chlorpheniramine,
naloxone.
Contd….
 Inverse agonist: An agent which activates a receptor to produce an effect in the

opposite direction to that of the agonist. Inverse agonists have affinity but intrinsic
activity with a minus sign (IA between 0 and –1). e.g. DMCM (on benzodiazepine
receptor), chlorpheniramine (on H1 histamine receptor).
 Partial agonist: An agent which activates a receptor to produce submaximal effect but
antagonizes the action of a full agonist. Partial agonists have affinity and submaximal
intrinsic activity (IA between 0 and 1). e.g. dichloroisoproterenol (on β adrenergic
receptor), pentazocine (on μ opioid receptor).
Contd….
MEDICAL; 2011.
Classification
The IUPHAR ( International Union of Pharmacological Science) system broadly

classifies receptors as:
1. Pharmacological ( Mediator based e.g. Nor Epinephrine, Insulin)
2. Biochemical & Biophysical (Second messenger based e.g. cAMP, PLC)
3. Molecular or Structural (Subunit Composition e.g. 5HT1A)
4. Anatomical ( Tissue e.g. muscle or ganglionic Ach or Cellular e.g. Cell surface
or intracellular)
IUPHAR/ GUIDE TO PHARMACOLOGY

Transducer
Mechanisms
o These are complex multistep processes that provide for amplification and integration
of concurrently received extra- and intracellular signals at each step.
o Only a handful of transducer pathways are shared by large number of receptors, the cell
is able to generate an integrated response reflecting the sum total of diverse signal input.
H.P RANG, J.M. RITTER, R.J. FLOWER, G.HENDERSON: RANG & DALE’S PHARMACOLOGY; 8TH EDITION. CHINA: ELSEVIER; 2016.
Contd….
The transducer mechanisms classifies receptors into 4 major categories:

1. Ligand Gated Ion channel receptor
2. G-Protein Coupled Receptors (GPCRs)
3. Kinase-linked and related receptors
4. Receptors regulating gene expression ( Transcription factors, Nuclear
factors)
H.P RANG, J.M. RITTER, R.J. FLOWER, G.HENDERSON: RANG & DALE’S PHARMACOLOGY; 8TH EDITION. CHINA: ELSEVIER; 2016
Ligand-gated ion
channels
 Also known as Ionotropic receptors.
 These are the receptors on which fast neurotransmitters act.
 These mediate fast synaptic transmission, on a millisecond time scale, in the nervous system
and at the somatic neuromuscular junction.
 Typical example of this is Nicotinic Acetylcholine receptor at NM junction.
 Other examples include GABAA , 5HT3 receptors, Glycine receptors, IP3 receptors, Ionotropic
Glutamate receptors, Purinergic PAX, etc.
Contd….
 These are integral membrane proteins that contain a pore which allows the regulated flow
of selected ions across the plasma membrane.
 Ion flux is passive and driven by the electrochemical gradient for the permeant ions.
 These channels are open, or gated, by the binding of a neurotransmitter to an orthosteric

site(s)
that triggers a conformational change that results in the conducting state.
 Modulation of gating can occur by the binding of endogenous, or exogenous, modulators

to
allosteric sites.
Molecular structure
 The nicotinic acetylcholine receptor consists of a pentameric
assembly of four subunits, termed α, β, γ and δ, each of molecular
weight 40–58 kDa.
 The pentameric structure (2α, β, γ, δ) possesses two acetylcholine
binding sites, each lying at the interface between one of the two
α subunits and its neighbour.
 Both must bind acetylcholine molecules in order for the receptor
to be
activated.
 Each subunit contains four membrane-spanning α-helices, inserted
into the membrane.
Contd….
Mechanism of Action:
 The five helices that form the pore are sharply
kinked inwards halfway through the membrane,
forming a constriction.
 When two acetylcholine molecules bind to the binding

sites, a conformational change occurs in the extracellular
part of the receptor.
 This twists the α subunits, causing the kinked helical

segments to swivel out of the way, thus opening the
channel.
Contd….
Clinical Significance:
 Nicotinic Ach receptors and Glutamate receptors are responsible for the majority of
synaptic transmission by neurons in CNS as well as in the periphery. So, they help in
generation and propagation in nerve impulses.
 IP3 sensitive Ca2+ channels are responsible for release of Ca2+ from ER and this can be
blocked by drugs in treatment of Malignant Hyperthermia.
 The Sulfonylurea Receptor ‘SUR 1’ regulates the ATP-dependent K+ channels are the
prime target of oral hypoglycemic drugs in treatment of Type II DM.
MEDICAL; 2011.
G-protein coupled receptors
(GPCRs):
 These are also known as Metabotropic or 7- Transmembrane (7TM) receptors.
 G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in

the human genome.
 Humans express over 800 GPCRs that make up the third largest family of genes in
humans.
 Examples include chemoreceptors in olfaction, taste & vision, Musuranic AchRs,

Adrenoceptors, dopamine receptors, GABAB many peptide and purine receptors and many
Orphan receptors.
MEDICAL; 2011.
Contd….
 They are membrane receptors that are coupled to intracellular effector systems primarily via
a G protein.
 G proteins are heterotrimeric GTP-binding regulatory proteins.
 G proteins are signal transducers that convey the information that agonist is bound to the
receptor from the receptor to one or more effector proteins.
 G–protein-regulated effectors include enzymes such as adenylyl cyclase, phospholipase C,

cyclic GMP, phosphodiesterase (PDE6), and membrane ion channels selective for Ca2+ and K+.
MEDICAL; 2011.
Classification of
GPCRs
 On the basis of sequence homology, GPCRs are classified into six classes. These classes
and their prototype members were as follows:
 Class A (rhodopsin-like),
 Class B (secretin receptor family),
 Class C (metabotropic glutamate),
 Class D (fungal mating pheromone receptors),
 Class E (cyclic AMP receptors) and
 Class F (frizzled/smoothened).
 Of these, classes D and E are not found in vertebrates

Contd….
Contd….
An alternative classification scheme "GRAFS" divides GPCRs into five classes:
o Glutamate family (class C): eg. metabotropic glutamate receptors, a calcium-sensing
receptor and GABAB receptors.
o Rhodopsin family (class A): eg. neurotransmitters, peptides and hormones,
olfactory receptors, visual pigments, taste type 2 receptors.
o Adhesion family: These are phylogenetically realted to class B receptors, from
which they
differ by possessing large extracellular N-terminal.
o Frizzled family: Consists of 10 Frizzled proteins (FZD(1-10)) and Smoothened
(SMO).
o Secretin family: These are encoded by 15 genes in humans. The ligands for receptors in
this family are: glucagon, glucagon-like peptides (GLP-1, GLP-2), GIP, secretin, VIP,
pituitary adenylate cyclase-activating polypeptide (PACAP) and GHRH.

Molecular
structure
 The first GPCR to be fully characterised was the
β adrenoceptor, which was cloned in 1986.
 The GPCR molecule has 7 α-helical membrane spanning

hydrophobic amino acid (AA) segments which run into
3 extracellular and 3 intracellular loops.
 Two binding sites: agonist binding and G-protein

coupling.
 The third intracellular loop interacts with the G

protein.
G-
proteins
 These comprise a family of membrane-resident proteins whose function is to recognise
activated GPCRs and pass on the message to the effector systems that generate a
cellular response.
 They are called G proteins because of their interaction with the guanine nucleotides, GTP
and GDP.
 G proteins consist of three subunits: α, β and γ.
 Guanine nucleotides bind to the α subunit, which has enzymatic (GTPase) activity,
catalysing the conversion of GTP to GDP.
 The β and γ subunits remain together as a βγ complex.
H.P RANG, J.M. RITTER, R.J. FLOWER, G.HENDERSON: RANG & DALE’S PHARMACOLOGY; 8TH EDITION. CHINA: ELSEVIER;
2016
Contd….
 In the basal state of the receptor-heterotrimer complex, the α subunit contains bound GDP
and the α-GDP:βγ complex is bound to the unliganded receptor.
 The G protein family is comprised of 23 α subunits, 7 β subunits, and 12 γ

subunits.
MEDICAL; 2011.
Contd….
 A number of G-proteins distinguished by their α subunits have been described. The

important ones with their action on the effector are:
1. Gs- Adenylyl cyclase activation, Ca+ channel opening. (Activated by cholera toxin)
2. Gi- Adenylyl cyclase inhibition, K+ channel opening. (Blocked by pertussis toxin)
3. Go- Ca+ channel inhibiton.
4. Gq- Phospholipase C activation.
Contd….
The following couplers have been associated with different G
receptors: Receptor Coupler
Muscuranic M2 Gi, Go
Muscuranic M1, M3 Gq
Dopamine D2 Gi, Go
β-adrenergic Gs
α1- adrenergic Gq
α2- adrenergic Gi, Go
 In addition, Gs is the coupler for histamine H2, serotonin 5HT4-7 and many
more.
 Gi is utilized by opioid, cannabinoid and some other receptors.
Mechanism of
Action
 When an agonist binds to a GPCR, there is a conformational change in the receptor.
 This causes the α subunit to exchange its bound GDP for GTP.
 Binding of GTP activates the α subunit and causes it to release both the βγ dimer and the
receptor.
 Both the GTP bound α subunit and the βγ heterodimer become active signaling
molecules.
GOODMAN, GILMAN, L.BRUTON: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS; 12TH EDITION, NEW YORK: MCGRAW
HILL MEDICAL; 2011.
Contd….
MEDICAL; 2011.
Contd….
MEDICAL; 2011
Effector
pathways
The main targets for G proteins, through which GPCR control different aspects of cell
function are:
o Adenylyl cyclase, the enzyme responsible for cAMP formation.
o Phospholipase C, the enzyme responsible for inositol phosphate and diacylglycerol

(DAG) formation.
o Ion channels, particularly calcium and potassium channels.
Contd
….
Adenylyl cyclase/cAMP
pathway:
intracellular
accumulation of Activates Protein
Activation of AC Kinase (PKA)
second messenger
cAMP
Increased contractility/ impulse

Phosphorylates and alters the function of
generation, relaxation,
many enzymes, ion channels, transporters,
glycogenolysis, lipolysis, secretion
transcription factors and structural proteins
of hormones, etc.
2016
Contd….
Some examples of role of increased cAMP are:
 β-adrenoceptor activation: helps in increasing blood glucose.

 Phosphorylation of voltage gated Ca2+ channels in heart muscle cells increases the force
of contraction of the heart.
 In smooth muscle, cAMP phosphorylates (thereby inactivating), myosin light-chain
kinase, required for contraction. This accounts for the smooth muscle relaxation.
2016
Contd
….
Phospholipase C : IP3-DAG pathway:
Activation of
phospholipase Cβ
Hydrolyses the membrane
PIP2 to generate IP3 and
DAG
IP3 diffuses to cytosol and mobilises
calcium from ER whereas, DAG
stays in the membrane and recruits
and activates PKc.
The activated PKc phosphorylates

many intracellular proteins and
mediated various physiological
responses.
2016
Contd….
• Another major function of G protein-coupled receptors is to control ion channel
function directly.
• These do not involve second messengers such as cAMP or inositol phosphates.
• Examples:
• In Cardiac muscles, mAChRs enhance K+ permeability.
• In neurons, inhibitory drugs such as opioid analgesics reduce excitability by opening
certain K+ channels or by inhibiting voltage-activated Ca2+ channels and thus reducing
neurotransmitter release.
Major functional pathways of GPCR transduction
Adenylyl cyclase: cAMP Phospholipase IP3-DAG Channel regulation
Increases Increase Ca2+ Decrease Ca2+ Increase K+

Decreases
Adrenergic-β Adrenergic-α2 Adrenergic-α1 Adrenergic-β1 Dopamine-D2 Adrenergic-α2
Histamine- Muscuranic-M2 Histamine-H1 (Heart, Sk. GABAB Muscuranic-M2
Muscle)
H2
Dopamine-D1 Dopamine-D2 Muscuranic-M1, M3 Opioid- κ Dopamine-D2
Glucagon 5-HT1 5-HT2 Adenosine-A1 5-HT1A
FSH & LH GABAB Vasopressin-oxytocin Somtostatin GABAB
ACTH Opioid- µ, δ Bradykinin-B2 Opioid- µ, δ
TSH Angiotensin- Angiotensin-AT1 Adenosine-A1
Prostaglandin AT1 Prostaglandin-FP, EP1
- EP2 EP3
Prostaglandin-
Prostacyclin- Somatostatin Thromboxane- TP
EP3
IP Adenosine- Adenosine-A1 Leukotriene BLT, cys LT
A2 Cholecystokinin-Gastrin
PAF
Contd….
 Approx 45% of all pharmaceutical drugs are known to target these
GPCRs.
 Examples include:
Contd….
Contd….
Abnormal G protein signalling can occur due to:
a) Bacterial toxins. Eg. Cholera and Pertussis toxin.

b) Gene mutations:
1. Gain of function mutation: can lead to development of Congenital Nightblindness
(rhodopsin), Familial Precocious puberty (LH), Familial Hypocalcemia (Ca2+ sensing), etc.
2. Loss of function mutation: can lead to development of Retinitis Pigmentosa (rhodopsin),
Diabetes
Insipidus (V2), Hypocalciuric Hypercalcemia (Ca2+ sensing), etc.
c) GPCR Misfoldings: can lead to diseases like Nephrogenic DI (V2R),

Hypogonadotrophic Hypogonadism (GnRHR),etc.
MEDICAL; 2011
Kinase-linked and related
receptors
• Diverse group of physiological membrane receptors.
• They have extracellular ligand binding domains and an intrinsic enzymatic activity on
the cytoplasmic surface of the cell.
• Most are activated by a wide variety of protein mediators, including growth factors and
cytokines, hormones such as insulin and leptin.
• Here, the effects are exerted mainly at the level of gene transcription.
Contd….
The main types are as follows:

1. Receptor tyrosine kinases (RTKs)
2. Cytokine receptors ( JAK-STAT Receptor)
3. Receptor serine/threonine kinases
4. Others ( Toll-like Receptors, TNF-α)
Contd….
Receptor tyrosine kinases (RTKs):
 These molecules consist of single polypeptide chains.
 Have large, cysteine-rich extracellular domains.
 Have short transmembrane domains.
 The intracellular region containing one (or in some cases two) protein
tyrosine kinase domains.
 Examples include receptors for hormones such as insulin, for

multiple
growth factors such as EGF, PDGF, NGF, FGF, VEGF, and ephrins.
HILL MEDICAL; 2011
Mechanism of
action
Contd….
Cytokine receptors ( JAK-STAT Receptor):
• These receptors signal to the nucleus by a more direct manner than the receptor tyrosine
kinases.
• These receptors have no intrinsic enzymatic activity.
• The intracellular domain binds a separate, intracellular tryosine kinase termed a Janus kinase
(JAK).
• JAKs phosphorylate other proteins termed signal transducers and activators of
transcription
(STATs).
• Examples include receptors for cytokines such as γ-interferon, hormones like
growth hormone and prolactin.
MEDICAL; 2011
Mechanism of
action
2016
Contd….
Receptor serine/threonine kinases:
 This smaller class is similar in structure to RTKs.
 However, they phosphorylate serine and/or threonine residues rather than tyrosine.
 The activated receptor on ligand binding, phosphorylates a gene regulatory protein termed
a
Smad.
 The main example is the receptor for transforming growth factor (TGF-β).
MEDICAL; 2011
Contd….
Other receptors include:
 Toll-Like Receptors:
• Signaling related to the innate immune system.
• Highly expressed in hematopoeitic cells.
• Ligands comprise of a multitude of pathogen products including lipids,
peptidoglycans, lipopeptides, and viruses.
• Activation of these receptors produces an inflammatory response to the
pathogenic microorganisms.
 Tumor Necrosis Factor α (TNF-α): Eg: Signaling to the NF-κB transcription factors.
HILL MEDICAL; 2011
Contd….
 These are key regulators of critical cellular processes, such as proliferation and
differentiation, cell survival and metabolism, cell migration and cell cycle control.
 RTKs are seen as drug targets in many types of cancer and other disease states like
inflammation, neurodegeneration, atherosclerosis.
 Many diseases result from genetic changes or abnormalities that either alter the activity
and/or regulation of RTKs.
IUPHAR/ GUIDE TO PHARMACOLGY

Contd….
Few classic examples of Drugs that act at receptors in this diverse family:
1. Insulin for the treatment of diabetes mellitus.
2. Imatinib used to treat chronic myelogenous leukemia and several solid tumors
with dysregulated tyrosine kinases.
3. Humanized monoclonal antibodies to TNF-α itself, such as infiximab and
adalimumab, are important for the treatment of rheumatoid arthritis and Crohn’s disease.
MEDICAL; 2011
Receptors regulating gene
expression
 Also called as Nuclear Receptors (NR).
 NRs can directly interact with DNA, so called ligand activated transcription factors.
 These transduce signals by modifying gene transcription.
 Examples are receptors for steroid hormones, glucocorticoids, mineralocorticoids, thyroid

hormone, Vit D, RXR, LXR, PPAR, etc.
2016
Contd….
Molecular Structure:
 The N-terminal domain displays the most
heterogeneity. It harbours the AF1
(activation function 1) site.
 The core domain of the receptor is highly
conserved and consists of the structure responsible
for DNA recognition and binding.
 It is the highly flexible hinge region in the
molecule that allows it to dimerise with other
NRs.
 The C-terminal domain contains the ligand-
binding
module and is specific to each class of receptor. Diagram of a nuclear receptor
Classification
Mechanism of
Action
Cont
d
2016
Contd…
.Clinical Significance:
1. NRs are very important drug targets, being responsible for the biological effects of
approximately 10–15% of all prescription drugs.
2. NRs also regulate expression of many drug metabolising enzymes and transporters.
3. Many illnesses are associated with malfunctioning of the NR system, including

inflammation, cancer, diabetes, cardiovascular disease, obesity and reproductive disorders.
Regulation of
Receptors
 Receptors exist in a dynamic state, i.e. their density and efficacy to elicit a response is subject
to regulation by the level of on-going activity, feedback from their own signal output and
other pathophysiological influences.
 The mechanisms involved may be unmasking of receptors or their proliferation (up
regulation)
or accentuation of signal amplification by the transducer.
 Eg. – Estrogens increase the density of oxytocin receptors on the myometrium, and the
sensitivity of uterus to contractile action of oxytocin increases progressively during the
third trimester of pregnancy, especially near term.
Contd….
 Conversely, continued / intense receptor stimulation causes desensitization or refractoriness:

the receptor becomes less efficient in transducing response to the agonist.
 The mechanisms by which this is brought about is:
 Masking or internalization of the receptor or impaired coupling of the transducer to
the receptor. Eg. In case of β adrenergic receptors.
 Decreased synthesis/ increased destruction of receptors (down regulation). Eg. In
tyrosine
kinase receptors.
 Eg. Includes patients of bronchial asthma being treated continuously with β adrenergic
agonists gradually become less responsive.
Function
s
These are:
1. To propagate regulatory signals from outside to inside the effector cell when the
molecular
species carrying the signal cannot itself penetrate the cell membrane.
2. To amplify the signal.
3. To integrate various extracellular and intracellular regulatory signals.
4. To adapt to short term and long term changes in the regulatory melieu and maintain
homeostasis.
Recent
Advances
1. YM-254890 and FR900359:
 These are related cyclic depsi-peptide natural products.
 Specifically and potently inhibit the Gq subfamily of G proteins.
 Is targeted in treatment of CNS disorders.
2. GPR83:
 Is currently classified as an orphan receptor.
 Mainly localised in the mouse to the CNS.
 It has been implicated in behavior, learning, and metabolic regulation.
 A biologically active peptide, PEN is now identified as a ligand activating
GPR83.
1. NISHIMURA A. ET. AL.(2010) STRUCTURAL BASIS FOR THE SPECIFIC INHIBITION OF HETEROTRIMERIC GQ PROTEIN BY A SMALL MOLECULE. PROC NATL ACAD SCI; 107(31): 13666–13671.
2. GOMES I ET AL. (2016). IDENTIFICATION OF GPR83 AS THE RECEPTOR FOR THE NEUROENDOCRINE PEPTIDE PEN.SCI. SIGNAL. 9(425): RA43.
Contd….
1. GPR68:
 G-protein coupled receptor belongs to a proton sensing family detecting acidic pH.
 A potent GPR86 positive allosteric modulator (PAM) named ogerin is identified.
 GPR68 plays a role in anxiety.
 This suggests a potential new drug target in this and related CNS disorders.
2. CSF1R:
 Inhibition of CSF1R by a tyrosine kinase inhibitor results in the blockade of
microglial proliferation on transgenic mouse model of Alzheimer's-like pathology.
 There was improved memory and behavioural performance as well as prevention
of synaptic degeneration.
 This suggests the therapeutic strategy of modifying CSF1R activation could
ameliorate Alzheimer's disease.
1. HUANG XP, KARPIAK J, KROEZE WK ET AL. (2015). ALLOSTERIC LIGANDS FOR THE PHARMACOLOGICALLY DARK RECEPTORS GPR68 AND GPR65 NATURE 527: 477-83.
2. OLMOS-ALONSO A, SCHETTERS ST, SRI S ET AL. (2016). PHARMACOLOGICAL TARGETING OF CSF1R INHIBITS MICROGLIAL PROLIFERATION AND PREVENTS THE PROGRESSION OF ALZHEIMER'S-LIKE PATHOLOGY
BRAIN : EPUB JAN 8
Contd….
1. Sigma receptor:
 It has been a ‘receptor-in-waiting’.
 Revealed as ‘fourth’ opioid receptor.
 Responds to nociceptin/orphanin.
 Has functional impact, in particular in the nervous and cardiovascular systems.
2. Sigma-2 Receptors:
 Receptor activation produced both transient and sustained increases in Ca2+ and cytotoxic
effects.
 Sigma-2 agonists induced apoptosis in drug-resistant cancer cells.
 Also, enhanced the potency of DNA damaging agents.
 Sigma-2 receptor agonists may be useful in treatment of drug-resistant cancers.
1. SCHMIDT HR, ZHENG S, GURPINAR E ET AL. (2016). CRYSTAL STRUCTURE OF THE HUMAN Σ1 RECEPTOR. NATURE 532(7600): 527-530.
2. WAYNE D BOWEN, ET AL. SIGMA RECEPTORS: RECENT ADVANCES AND NEW CLINICAL POTENTIALS. PHARMACEUTICA ACTA HELVETIAE, VOL 74, ISSUES 2–3, 2000: 211–218.
Summar
y
 Receptors are molecules which are essential for majority of biochemical and
metabolic processes in the body.
 Extensive research is being done on receptor pharmacology to find out new class
of receptors.
 Newer Drug molecules that target different receptor proteins and alter their
physiology are
needed to be searched for.
 Discovery about mechanism of orphan receptors can lead to drug development for
the effective treatment of diseases.
Reference
s
1. Goodman, Gilman, L.Bruton: The Pharmacological Basis of
THERAPEUTICS; 12 th Edition. New York: McGraw Hill Medical; 2011.
2. H.P Rang, J.M. Ritter, R.J. Flower, G.Henderson: RANG & DALE’S
Pharmacology; 8 Edition. China: Elsevier; 2016.
th
3. K.D Tripathi: Essentials of Medical Pharmacology; 7 th Edition. New Delhi: Jaypee

Brothers; 2013.
4. IUPHAR/BPS. Guide to Pharmacology.

www.guidetopharmacology.org/
5. Nishimura A. et. al.(2010) Structural basis for the specific inhibition
of heterotrimeric Gq protein by a small molecule. Proc Natl Acad
Sci; 107(31): 13666–13671.
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DRUG

2. John N. Langley is known as one of the fathers of the chemical receptor

3. P. Ehrlich designated the term ‘Receptor’ in 1900.

 The receptor is believed to exist in two

 In the case of majority of receptors, the Ri state is

 Antagonist: An agent which prevents the action of an agonist on a receptor or the

 Inverse agonist: An agent which activates a receptor to produce an effect in the

The IUPHAR ( International Union of Pharmacological Science) system broadly

IUPHAR/ GUIDE TO PHARMACOLOGY

The transducer mechanisms classifies receptors into 4 major categories:

 These channels are open, or gated, by the binding of a neurotransmitter to an orthosteric

 Modulation of gating can occur by the binding of endogenous, or exogenous, modulators

 When two acetylcholine molecules bind to the binding

 This twists the α subunits, causing the kinked helical

 G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in

 Examples include chemoreceptors in olfaction, taste & vision, Musuranic AchRs,

 G proteins are heterotrimeric GTP-binding regulatory proteins.

 G–protein-regulated effectors include enzymes such as adenylyl cyclase, phospholipase C,

IUPHAR/ GUIDE TO PHARMACOLOGY

IUPHAR/ GUIDE TO PHARMACOLOGY

 The GPCR molecule has 7 α-helical membrane spanning

 Two binding sites: agonist binding and G-protein

 The third intracellular loop interacts with the G

 The G protein family is comprised of 23 α subunits, 7 β subunits, and 12 γ

 A number of G-proteins distinguished by their α subunits have been described. The

o Phospholipase C, the enzyme responsible for inositol phosphate and diacylglycerol

o Ion channels, particularly calcium and potassium channels.

Increased contractility/ impulse

Some examples of role of increased cAMP are:

 β-adrenoceptor activation: helps in increasing blood glucose.

The activated PKc phosphorylates

• These do not involve second messengers such as cAMP or inositol phosphates.

Increases Increase Ca2+ Decrease Ca2+ Increase K+

a) Bacterial toxins. Eg. Cholera and Pertussis toxin.

c) GPCR Misfoldings: can lead to diseases like Nephrogenic DI (V2R),

The main types are as follows:

 Examples include receptors for hormones such as insulin, for

IUPHAR/ GUIDE TO PHARMACOLGY

 These transduce signals by modifying gene transcription.

 Examples are receptors for steroid hormones, glucocorticoids, mineralocorticoids, thyroid

3. Many illnesses are associated with malfunctioning of the NR system, including

 Conversely, continued / intense receptor stimulation causes desensitization or refractoriness:

3. K.D Tripathi: Essentials of Medical Pharmacology; 7 th Edition. New Delhi: Jaypee

4. IUPHAR/BPS. Guide to Pharmacology.

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