Receptor types, mechanism, receptor pharmacology, drug receptor interactions, theories of receptor pharmacology, spare receptors and new concepts like biased agonism
2. CONTENTS
Introduction
Targets for drug binding
Types of receptors
Determinants of drug activity
Receptor theories
Drug receptor interactions
Desensitisation and
tachyphylaxis
Conclusion
3. HISTORY
1878 – John Langley
1905 - Receptive substance on surface of skeletal
muscle mediate drug action. Different in different
species
Paul Ehrlich designated 'receptor‘ to be anchoring
group of the protoplasmic molecule for the
administered compound
“Corpora non agunt nisi fiata”
4. 1948 - Ahlquist showed the differential action of adrenaline
& demonstrated its effects on two distinct receptor
populations & the theory of receptor-mediated drug
interactions gained acceptance
1970s - Pharmacology entered a new phase following the
development of receptor-labelling techniques which made
it possible to extract and purify the receptor material.
6. Drug is any substance or
product that is used for
diagnosis, prevention,
treatment/cure of a disease
or is intended to be used to
modify or explore
physiological systems or
pathological states for
the benefit of the
7. Cellular macromolecule, or an assembly of
macromolecules, mainly protein in nature
present on the surface of the cell membrane
or inside the cell, concerned directly and
specifically in chemical signaling between and
within the cells
8. TYPES OF RECEPTORS
Ligand Gated Ion Channels
G-Protein Coupled receptors
Enzyme Linked receptors
Nuclear receptors
9. LIGAND GATED ION CHANNELS
Ionotropic Receptors
Typically receptors on which
fast neurotransmitters act
Timescale: Milliseconds
Localization: Membrane
Effector: Ion Channel
Coupling: Direct
Gating mechanism: conformational change occurs in
extracellular part of the receptor
Examples: Nicotinic Ach Receptor, GABA-A Receptor,
Glutamate Receptor, Glycine receptor, 5–HT3, AMPA &
kinate receptors
10. VOLTAGE OPERATED CHANNELS
These channels open when the cell membrane
is depolarised. They underlie the mechanism of
membrane excitability
Activation induced by membrane depolarisation
is short lasting, even if the depolarisation is
maintained
The most important channels in this group are
selective sodium, potassium or calcium
channels
11.
12. G – PROTEIN – COUPLED RECEPTORS
Largest family
Metabotropic or 7–Transmembrane/Heptahelical (α-
helices) receptors
Extracellular N-terminal domain and intracellular C-
terminal domain
3rd cytoplasmic loop couples to the G- Protein
Timescale : Seconds
Location : Membrane
Effector : Channel or Enzyme
Coupling : G- Protein
Examples : adrenoceptors, Muscarinic Ach, histamine,
serotonin, opioid, cannabinoid, amine, peptide, prostanoid
17. Ion Channels like K⁺ and Ca⁺⁺ channels are controlled by
direct interaction between the βγ-subunit of G0 and the
channel
Phospholipase A2(formation of arachidonic acid and
eicosanoids)
Rho A/Rho kinase, a system that controls the activity of
many signaling pathways controlling cell growth and
proliferation, smooth muscle contraction, etc.
Mitogen-activated protein kinase (MAP kinase), activated
by cytokines and growth factors acting on kinase-linked
receptors and by GPCR ligands. Controls processes
involved in cell division, apoptosis and tissue
regeneration
18. KINASE LINKED AND RELATED RECEPTORS
Large, heterogenous group responding mainly
to protein mediators.
Timescale : Hours
Location : Membrane
Effector : Protein Kinases
Coupling : Direct
Examples : Insulin, Growth Factors, Cytokine,
ANF receptors
19.
20. NUCLEAR RECEPTORS
Two main categories:
1) Present in the cytoplasm, form homodimers and
migrate to the nucleus. Their ligands are mainly
endocrine in nature (e.g. steroid hormones)
2) constitutively present in the nucleus and form
heterodimers with the retinoid X receptor. Their ligands
are usually lipids (e.g. fatty acids).
A third subgroup transduce mainly endocrine signals but
function as heterodimers with retinoid X receptor (e.g.
thyroid hormone).
ligand-receptor complexes initiate changes in gene transcription
by binding to hormone response elements in gene
promoters and recruiting co-activator or co-repressor factors
21.
22. DRUG RECEPTOR INTERACTIONS
LIGAND: Any molecule which attaches selectively
to particular receptor
AFFINITY: Capability of drug to bind to the
receptor and form receptor complex
INTRINSIC ACTIVITY: Ability of the drug to
trigger the pharmacological response after forming
complex
23. DETERMINANTS OF DRUG ACTIVITY
Efficacy: The ‘strength’ of the agonist–receptor
complex in evoking a response of the tissue
Potency: Amount of drug needed to produce an
effect.
25. OCCUPATION THEORY, CLARK’S (1926)
Drugs act on independent binding sites and activate them,
resulting in a biological response that is proportional to the
amount of drug-receptor complex formed.
D + R DR RESPONSE
Intensity of pharmacological effect is directly proportional to
number of receptors occupied
The response ceases when this complex dissociates
Maximal response occurs when all the receptors are
occupied at equilibrium
Limitations ??
26. THE INDUCED-FIT THEORY, DANIEL KOSHLAND (1958)
States that the morphology of the binding site is not necessarily
complementary to the preferred conformation of the ligand
Binding produces a mutual plastic molding of both the ligand
and the receptor as a dynamic process.
The conformational change produced by the mutually induced
fit in the receptor macromolecule is then translated into the
biological effect, eliminating the rigid and obsolete “ key and
lock” concept
Agonist induces conformational change – response
Antagonist does not induce conformational change – no
response
27. PATON’S RATE THEORY (1961)
The response is proportional to the rate of drug-Receptor
complex formation
Effect is produced by the drug molecules based on the
rates of association and dissociation of drugs to and from
the receptors
Antagonists act much more slowly than agonists do and
hence the rate of dissociation is inversely proportional to
the potencies of antagonists while is directly proportional
to the agonists
Type of effect is independent of number of receptors rather
rate of binding and release from the receptor.
28. THE TWO-STATE (MULTISTATE) RECEPTOR MODEL
Developed on the basis of the kinetics of
competitive and allosteric inhibition
It postulates that a receptor, regardless of the
presence or absence of a ligand, exists in two
distinct states: the R(active) and R* (inactive)
states
R and R* are in equilibrium (equilibrium constant
L), which defines the basal activity of the receptor
Occupied receptor can switch from its ‘resting’ (R)
state to an activated (R*) state, R* being favored
by binding of an agonist but not an antagonist
29. Added drug encounters an equilibrium
mixture of R and R*
If it has a higher affinity for R* than for R,
the drug will cause a shift of the equilibrium
towards R* (i.e. it will promote activation
and be classed as an agonist)
If its preference for R* is very large, nearly all
the occupied receptors will adopt the R* conformation
and the drug will be a full agonist (positive efficacy)
Shows only a modest degree of selectivity for R*, a smaller
proportion of occupied receptors will adopt the R*
conformation(partial agonist
Shows no preference, the prevailing R:R* equilibrium will not be
disturbed and the drug will be a neutral antagonist(zero efficacy)
Shows selectivity for R it will shift the equilibrium towards R and
be an inverse agonist (negative efficacy)
30. AGONIST
A drug that binds to physiological receptor and
mimic the regulatory effects of endogenous
substance.
It has high affinity and high intrinsic activity
31.
32. TYPES OF AGONISM
Summation :- Two drugs eliciting same response, but
with different mechanism and their combined effect
is equal to their summation.
Aspirin Codiene
PG Opiods receptor
Analgesic+ Analgesic+
++
33. Additive: combined effect of two drugs acting by same
mechanism
Aspirin NSAIDS
PG PG
Analgesic+ Analgesic+
+ +
34. SYNERGISM (SUPRA ADDITIVE):-
The combined effect of two drug effect is higher than
either individual effect.
1.Sulfamethaxazole+ Trimethoprim
2. Levodopa + Carbidopa.
35. PARTIAL AGONIST
Full affinity + low intrinsic activity
Partly as effective as agonist
Greater affinity for RA than RI
Cannot produce a full biological
response at any concentration
ex: Pentazocine
36. INVERSE AGONIST:
Full affinity & intrinsic activity<0(0 to-1)
Inverse agonists bind with the constitutively active
receptors, stabilize them, and thus reduce the activity
(negative intrinsic activity).
Eg. Beta carbolines on BZD receptor
Chlorpheneramine on H1,
Risperidone/clozapine/chlorpromazine on 5-HT2a
Ziprasidone/olanzapine on 5-HT2c
37.
38. ANTAGONIST
A drug is said to be an antagonist when it binds to a
receptor and prevents (blocks or inhibits) a natural
compound or a drug to have an effect on the
receptor. An antagonist has no activity.
Types of Antagonism
1. Chemical antagonism
2. Physiological /Functional antagonism
3. Pharmacokinetic antagonism
4. Pharmacological antagonism
Competitive ( Reversible/irreversible)
Non competitive (Irreversible)
39. PHARMACOKINETIC ANTAGONISM
Antagonist effectively reduces the concentration of the
active drug at its site of action
Either by increased metabolic degradation, decreased
absorption or increased excretion
A- Calcium & tetracycline, Cholestyramine & warfarin/digoxin
D- Phenylbutazone & warfarin
M- ↑ Phenobarbital/rifampicin & warfarin, rifampicin & OCP
↓ ciprofloxacin/chloramphenicol/erythromycin &
theophylline
E- ↓ Probencid/aspirin/sulfonamides/thiazides/indomethacin &
penicillin/zidovudine, NSAIDS & methotrexate/ furosemide
40. PHARMACOLOGICAL ANTAGONISM
Competitive antagonism- Reversible
- Irreversible
1) Reversible antagonism
Antagonists that bind reversibly to the same receptor site as
that of an agonist
Surmountable
Shift of the agonist log concentration–effect curve to the right,
without change of slope or maximum effect
Linear relationship between agonist dose ratio and antagonist
concentration
41. Shift is expressed as a
dose ratio, r,
(the ratio by which the agonist
concentration has to be
increased in the presence of
the antagonist in order to restore
a given level of response)
Agonist reduces the rate of association of the antagonist
molecules
Consequently, the rate of dissociation temporarily exceeds
that of association, and the overall antagonist occupancy
falls.
42. IRREVERSIBLE ANTAGONISM
It occurs when the antagonist dissociates very slow or not
at all from the receptors results no change when the
agonist applied.
Antagonist effect cannot be
overcome even after increasing
the concentration of agonist
Occurs with drugs that possess
reactive groups that form
covalent bonds with the receptor
Aspirin, omeprazole and MAO inhibitors
43.
44. SPARE RECEPTORS
Receptors are said to be spare when, the maximal
response can be elicited by an agonist at a
concentration that does not result in 100% occupancy of
available receptors
Agonist has to bind only a portion of receptors for full effect-
increase sensitivity of the system
Many full agonists are capable of eliciting maximal responses
at very low occupancies, often less than 1%
Spare receptors, or a receptor reserve denotes that the pool
is larger than the number needed to evoke a full response
For a biological response economy of hormone or transmitter
secretion is thus achieved at the expense of providing more
receptors
45. DESENSITISATION & TACHYPHYLAXIS
TACHYPHYLAXIS
The effect of a drug gradually diminishes
when it is given continuously or repeatedly,
which often develops in the course of minutes
Tolerance- Gradual decrease in responsiveness to a drug,
taking days or weeks to develop.
Refractoriness is used to indicate loss of therapeutic
efficacy
Drug resistance is used to indicate loss of effectiveness
46. MECHANISM OF DESENSITISATION
Change in receptors- Ion channels
Translocation of receptors- beta adrenoreceptor
Exhaustion of mediators-amphetamines
Increased metabolic degradation-
alcohol/nitrates
Physiological adaptation-thiazide
47. BIASED AGONISM
Biased agonism, the ability of a receptor to differentially
activate downstream signaling pathways depending on
binding of a “biased” agonist compared to a “balanced” agonist
The ability of some ligands to selectively activate some
signaling pathways while blocking others
Peptides PACAP1-27 and PACAP1-38 activate PACAP (pituitary
cyclase-activating polypeptide type 1) receptors to elevate
cyclic AMP and increase production of IP3
The receptor is not the minimal unit of control of agonism, it is
the agonist-receptor complex that controls the ultimate
signaling event
Nature of the receptor-active state and the interaction of the
activated receptor with the multiple cytosolic signaling
48. Molecular dynamics predicts that when proteins such as
receptors change conformation, different regions of the
receptor change independently (i.e., the protein does not
form uniform global conformation)
Signaling protein s interact with different regions of the receptor
Unique receptor conformations stabilized by agonists most
likely will result in differential (biased) activation of cell signaling
pathways
Activation of a receptor that interacts with multiple signaling
components in a cell most likely will never produce equal
activation of all pathways
Functionally selective agonists are defined as having a
signaling bias different from that of the natural agonist
extracts elicited responses in tissues that were similar to those induced by nerve stimulation
A drug will not work unless it is bound’
drug molecules must be ‘bound’ to particular constituents of cells and tissues in order to produce an effect.
exceptions to Ehrlich’s dictum—
drugs that act without being bound to any tissue constituent (e.g.
osmotic diuretics, osmotic purgatives, antacids and heavy metal chelating agents).
Ehrlich envisaged molecules extending from cells that the body could use to distinguish and mount an immune response to foreign objects.
his approach was fist used successfully on the nicotinic acetylcholine receptor
. The fist was that the electric organs of many fihes, such as rays (Torpedo sp.) and electric eels (Electrophorus sp.) consist of modifidmuscle tissue in which the acetylcholine-sensitive membrane is extremely abundant, and these organs contain much larger amounts of acetylcholine receptor than anyother tissue.
second was that the venom of snakes of the cobra family contains polypeptides that bind with very high specifiity to nicotinic acetylcholine receptors. These
substances, known as α-toxins, can be labelled and used to assay the receptor content of tissues and tissue extractsest known is α-bungarotoxin Treatment of muscle or electric tissue with nonionic detergents renders the membrane-bound receptor protein soluble, and it can then be purifid by the technique of affiity chromatography. Similar approaches have now been used to purify a great many hormone and neurotransmitter receptors, as well as ion channels, carrier proteins and other kinds of target molecules.
Multiple subtypes of receptors now known, which has paved the way for clinically superior drugs
Na channel for la
Dhfr, ace, cox, immunophilin for cyclosporine,, 11 PDE subtypes exist Milrinone for CHF (PDE3), Rolipram for asthma (PDE 4) and Sidenafil (PDE 5)5fu- abnormal metabolite
Symport/antiport
These sites include external surfaces of skin and gastro-intestinal tract.
Endogenous agonist- hormone, NT, cytokines
Exo- drugs, chemicals
Act on the receptor and change in cell function producing a response
Pentameric Assembly of 4 types of subunits α, β, γ and δ
4 membrane spanning α-helices inserted into membrane
2 Ach binding sites, both must bind Ach molecules for receptor activation
Lining of central transmembrane pore formed by helical segments of each subunit (negatively charged AA). 5 helices sharply kinked inwards halfway, forming a constriction
Ach molecules bind, twists the α subunits, kinked helices either straighten out or swing out of the way, opening channel pore
Mutation of a critical residue in helix changes channel from being cation selective (excitatory) to being anion selective (typical of receptors for inhibitory transmitters like GABA)
Most excitatory neurotransmitters cause Increase in Na+ and K+ permeability
net inward current carried mainly by Na+
Depolarization of the membrane (probability to generate action potential)
Generally include one transmembrane helix that contains an abundance of basic (i.e. positively charged) AA
When membrane is depolarised, so that the interior of the cell becomes less negative, this region—the voltage sensor—moves slightly towards the outer surface of membrane, opening the channel
Inactivation happens when an intracellular appendage of the channel protein moves to plug the channel from the inside
Four six-helix domains consists of a single huge protein molecule, the domains being linked together by intracellular loops
lgCs appear to assume only two states whereas VOCs undergo a third state called refractory (inactivated) state.
Voltage gated channels have no major endogenous modulator (like Ach)
G protein is “guanine nucleotide binding protein”
The human genome includes genes encoding about 400 GPCRs (excluding odorant receptors), which constitute the commonest single class of targets for therapeutic drugs, and it is thought that many promising therapeutic drug targets of this type remain to be identified.
First GPCR to be fully characterized was β-Adrenoceptor.
Family A is largest. C smallest.
differ in length of extracellular N-terminus and location of agonist binding domain.
For small molecules, NA, the ligand-binding domain of class A receptors is buried in the cleft between the α-helical segments within the membrane. Peptide ligands bind more superficially to the extracellular domain
Coupling of the α subunit to an agonist-occupied receptor causes the bound GDP to exchange with intracellular GTP; the α–GTP complex then dissociates from the receptor and from the βγ complex, and interacts with a target protein (target 1, which may be an enzyme, such as adenylyl cyclase, or an ion channel)
The GTPase activity of the α subunit is increased when the target protein is bound, leading to hydrolysis of the bound GTP to GDP, whereupon the α
subunit reunites with βγ
catalyses formation of the intracellular messenger cAMP
cAMP activates various protein kinases that control cell function in many different ways by causing phosphorylation of various enzymes, carriers & other proteins
increased activity of voltage gated calcium channels in heart muscle cells. Phosphorylation of these channels increases the amount of Ca2+ entering the cell during the action potential, and thus increases the force of contraction of the heart
In smooth muscle, cAMP-dependent protein kinase phosphorylates (thereby inactivating) another enzyme, myosin-light-chain kinase, which is required for contraction. This accounts for the smooth muscle relaxation
Adenylyl cyclase can be activated directly by certain agents, including forskolin and fluoride ions
11 PDE subtypes exist; inhibited by theophylline & caffeine, Milrinone for CHF (PDE3), Rolipram for asthma (PDE 4) and Sidenafil (PDE 5)
Receptor-mediated activation of phospholipase C results in the cleavage of phosphatidylinositol bisphosphate (PIP2), forming diacylglycerol (DAG) (which activates protein kinase C) and inositol trisphosphate (IP3) (which releases intracellular Ca2+).
The role of inositol tetraphosphate (IP4), which is formed from IP3 and other inositol phosphates, is unclear, but it may facilitate Ca2+ entry through the plasma membrane.
IP3 is inactivated by dephosphorylation to inositol. DAG is converted to phosphatidic acid, and these two products are used to regenerate PI and PIP2.
many events, including contraction, secretion, enzyme activation and membrane hyperpolarization.
Direct G-protein–channel interaction first shown for cardiac muscle,
In cardiac muscle, mAChRs enhance K+ permeability (thus hyperpolarising the cells and inhibiting electrical activity). Similarly in neurons, many inhibitory drugs such as opioid analgesics reduce excitability by opening K+ channels or inhibiting Ca2+ channels.
By enhancing hypoxia-induced pulm artery vasoconstriction, Rho kinase active. thought to be imp pathogenesis of pulmonary HT. Specific Rho kinase inhibitors e.g. fasudil.
Rho–GDP, the resting form, is inactive, but when GDP–GTP exchange occurs, Rho is activated
and controls smooth muscle contraction, proliferation, angiogenesis and synaptic remodeling.
Toll like receptor
Janus kinase/signal transducers and activators of transcription
Generally involves dimerization autophosphorylation of tyrosine residues, act as acceptors for the SH2 domains of intracellular proteins
Involved mainly in events controlling cell growth and differentiation, and act indirectly by regulating gene transcription
Two important pathways are:– the Ras/Raf/ MAP kinase pathway - cell division, growth and differentiation.– the Jak/Stat pathway activated by many cytokines - controls the synthesis and release of many inflammatory mediators
Class I : In the absence of their ligand, these NRs are predominantly located in the cytoplasm, complexed with heat shock and other proteins and possibly reversibly attached to the cytoskeleton. Liganded receptors generally form homodimers and translocate to the nucleus, where they can transactivate or transrepress genes by binding to ‘positive’ or ‘negative’ hormone response elements. Large numbers of genes can be regulated in this way by a single ligand
Class II : LXR = Liver Oxysterol Receptor, FXR = Farsenoid (Bile acid) receptor, RXR = Retinoid receptor. Xenobiotic receptor = SXR. Bind to thiazolidinediones and Fibrates
Hybrid Class = Retinoic Acid receptor (RAR)
they bind only molecules of a certain precise type. angiotensin (Ch. 22). This peptide acts strongly on vascular smooth muscle, and on the kidney tubule, but has very little effect on other kinds of smooth muscle or on the intestinal epitheliumA
small chemical change, such as conversion of one of the amino acids in angiotensin from L to D form, or removal of one amino acid from the chain, can inactivate the molecule altogether, because the receptor fails to bind the altered form.
tricyclic antidepressant drugs act by blocking monoamine transporters but are notorious for producing side effects (e.g. dry mouth)
lower the potency of a drug and the higher the dose needed, the more likely it is that sites of action other than
the primary one will assume signifiance. In clinical terms, this is often associated with the appearance of unwanted side effects, of which no drug is free.
Classification of Ligands
a. agonist
b. partial agonist
c. antagonist
Effect of drug attributed to two factors
Efficacy Potential maximum therapeutic response that a drug can produce.
----Stephenson (1956) that describes effiacy
describes the tendency of the drug–receptor complex to adopt the active (AR*), rather than the resting (AR) state
Lower the potency of a drug and the higher chances of unwanted side effects, of which no drug is free
Emil fischer
FIRST model to be put forward by CLARK’S////
2--Quantifies the relationship b/w drug conc and observed effct// based on law of mass action kinetics
Limitations--Not all compounds that bind to a receptor elicit a response (Eg: antagonist).
does not explain about partial agonism, spare receptors concept of partial agonist, constitutional receptor activity, inverse agonism allosteric modulation.
lead to the development of agonist models of drug action --binding and activation phenomenon were explained by Ariëns and Stephenson in 1956 to account for the intrinsic activity (efficacy) of a drug (that is, its ability to induce an effect after binding).
The active site and substrate are exact matches for each other, similar to puzzle pieces fitting together. LOCK & KEY
This theory maintains that the active site and the substrate are, initially, not perfect matches for each other. Rather, the substrate induces a change in shape of the receptor
Similar to getting a hand in glove, placing ist finger might be difficult but once we pass the initial step the rest gets easier. The glove slides on easily
the duration of Receptor occupation determines whether a molecule is agonist, partial agonist of antagonist
Agonist- high K2 fast association and fast dissociation
Partial agonist- intermediate
Antagonist- low K2 fast association and slow dissociation
Correlation was poor
This explians phenomenon “ fade” which is observed when an agonist produces a very transient peak (E peak ) effect followed by steady state response (equilibrium effect i.e equal to E max). Hypothesis of Paton
as well as through interpretation of the results of direct binding experiments
This model has gained wide acceptance because it provides an explanation for the phenomenon of positive cooperativity often seen
with neurotransmitters, and is supported by studies of conformational mutants ofthereceptor with altered equilibrium.
Del Castillo & Katz in 1957 was based on their work on the action of acetylcholine at the motor endplate
effiacy as a property determined by the relative affiity of a ligand for R and R*,
In contrast to the classical occupation theory the agonist in the two-state model does not activate the receptor but shifts the equilibrium toward the Rform.
(1+1=2)
(1+1=3)
Even though drugs may occupy the same number of receptors, the magnitude of their effects may differ.
Naloxene on opioid receptors
saralasin on angiotensin receptors
naloxone and naltrexone are also partial inverse agonists at mu opioid receptors.
This constitutive activity is usually minimal in natural receptors but is markedly observed in wild type and mutated (naturally or induced) receptors. According to conventional two-state drug receptor interaction model, binding of a ligand may initiate activity (agonist with varying degrees of positive intrinsic activity) or prevent the effect of an agonist (antagonist with zero intrinsic activity).
metoprolol, carvedilol, propranolol, nebivolol, and bisoprolol, have shown inverse agonist activity
Nearly all H1 and H2 antihistaminics (antagonists) have been shown to be inverse agonists. Among the β-blockers, carvedilol and bucindolol demonstrate low level of inverse agonism as compared to propranolol and nadolol. Several antipsychotic drugs (D2 receptors antagonist), antihypertensive (AT1 receptor antagonists), antiserotoninergic drugs and opioid antagonists have significant inverse agonistic activity t
Chemical antagonism Ex: -heparin(-ve) protamine +ve, Chelating agents, infliximab(tnf), mab
interaction of two drugs whose opposing action in the body tend to cancel each other example – Histamine and Omeprazole on parietal cell of gastric mucosa.
D==selectively inhibits metabolism of the pharmacologically active (S) isomer
the reduction of the anticoagulant effect of warfarin when an agent that accelerates its hepatic metabolism, such as phenobarbital, is
the rate of absorption of the active drug from the gastrointestinal tract may be reduced, or the rate of renal excretion may be increased.
because the two are in competition, raising the agonist concentration can restore the agonist occupancy (and hence the tissue response). The antagonism is therefore said to be surmountable
hallmark
Atropine is a competitive antagonist of Ach.
Captopril competes with angiotensin 1 for
angiotensin convertin enzyme (ACE).
• Finasteride competes with testosterone for
Sa-reductase
agonist is able to displace the antagonist molecules from the receptors, although it cannot, of course, evict a bound antagonist molecule. Displacement occurs because, by occupying a proportion of the vacant receptors, the
Surmountability of the block by the antagonist may be important in practice, because it allows the functional effect of the agonist to be restored by an increase in concentration
These are mainly used as experimental tools
for investigating receptor function, and few are used clinically
AcetazolamideDisulfiramindomethacin - A- CyclooxygenasearbonicldehydeanhydraseOmeprazoleDigoxin; Theophylline
PropylthiouracilLovastatinSildenafilII. ION CHANNELSdehydrogenase- H• K• ATPase- Na• K• ATPase- Phosphodiesterase- Peroxidase in thyroid- HMG-CoA reductase- Phosphodiesterase-S
Log concentration–effect curves for a series of α-adrenoceptor agonists causing contraction of an isolated strip of rabbit aorta.
Phenylephrine is a full agonist.The others are partial agonists with different effiacies.
[B] The relationship between response and receptor occupancy for the series.
Note that the full agonist, phenylephrine, produces a near-maximal response when only about half the receptors are
occupied, fraction of receptors occupied (known as occupancy) as a function of drug concentration.
whereas partial agonists produce submaximal responses even when occupying all of the receptors.
The effiacy of tolazoline is so low that it is classifid as an α-adrenoceptor antagonist
Stephenson (1956), studying the actions of acetylcholine analogues
in isolated tissues, found that many full agonists were capable of eliciting maximal responses at very low occupancies, often less than
1%. Allows maximal response without total receptor occupancy –
Common with drugs that elicit smooth muscle contraction but less so for other types of receptor-mediated response, such as secretion, smooth
muscle relaxation or cardiac stimulation, where the effect is more nearly proportional to receptor occupancy.
agonist–receptor complexes can be minimized, with a lower concentration of hormone or neurotransmitter .
Well-established paradigm for GPCR sigNAL
relative efficacy of PACAP1-27 for cyclic AMP elevation is higher than that of PACAP1-38 but lower for elevation of IP3
clearly indicate that agonist activation of multiple signaling mechanisms is not uniform but rather is often ‘biased’ toward some but not all signaling
pathways
Activation of signalling pathways depends on the conformational change induced by the agonist receptor complex and it is highly selective
Not all agonist ll induce the same conformational change and hence lead to differential activation of downstream signalling pathways
3..Taking natural agonist for the receptor as useful point of reference ; this willhave a natural signaling bias
can be used as astandard with which other agonists can be compared
Extensive research done on Receptor pharmacology -lead to discovery of new drug targets for treatment of several diseases.
Still requires discovery of new receptor types and the mechanisms of many orphan receptors that can result in effective treatment of many diseases.
Much to be discovered about the nuclear receptors.