- Agonists, partial agonists, and inverse agonists are drug ligands that interact with receptors to elicit different cellular responses. Agonists mimic the effects of endogenous ligands, partial agonists produce submaximal effects, and inverse agonists stabilize receptors in their inactive state. - The two-state receptor model describes receptors existing in two conformational states (active and inactive) that ligands differentially stabilize. Biased agonism occurs when ligands preferentially activate different intracellular signaling pathways. - Key concepts include efficacy, intrinsic activity, and constitutive receptor activity. Partial agonists have efficacy below full agonists and produce submaximal responses even at full receptor occupancy. Inverse agonists suppress constitutive receptor activity.

1. Agonists, Partial agonists,
and Inverse agonists
Name -Jayita Das
18PCM2785
Department – Pharmacology and toxicology
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2. • Content:-
• Pharmacodynamic concept
• Drug Ligand Receptor interaction
Two state model
Biased Agonism
• Agonist
• Partial agonist
• Inverse agonist
• Reference
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3. • Pharmacodynamic Concepts:-
• The effect of most drugs result from their interaction with the
macromolecular components of the organism. These
interaction alters the function of the pertinent component
and initiate the biochemical and physiological changes that
are characteristic to the response of the drug. The term drug
receptor or drug target represent the cellular macromolecule
or macromolecular complex with which drug interacts to elicit
the cellular response i.e. change in cell function.
• John Newport Langley and Paul Ehrlich introduced the
concept of a receptor that would mediate drug action at the
beginning of the 20th century.
• Drugs receptor normally located on the surface of the cell or
may be located in the specific intracellular compartment.
• Example includes generally protein classes like GPCR,ligand
gated ion chanels,tyrosine kinase,nuclear receptor.
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8. • Agonist:-
• Drugs that bind to physiological receptor and mimic the
regulatory effect of the endogenous signalling compounds are
termed as agonist. If the drug binds to the same recognition
site as endogenous agonist than it is called primary agonist(full
agonist)2.
• Ex- Ach is an endogenous agonist and its primary agonist is
Bethanechol (2-- N,N,N-trimethyl- 1-propanaminium; Carbamyl-
β-methylcholine) , carbochol etc. Efficacy = 1
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9. • Allosteric agonist binds to the different site of the receptor
called allotopic site, Ex BZD receptor. GABAa stimulates
essentially complete opening of the GABAa channel, but
binding of a benzodiazepine shifts the binding curve of GABA
to the left, ie, a level of GABAa that previously caused a 25 %
of max channel opening now has 50% or 100%. As such a
benzodiazepine can never cause a greater opening than
GABA, just cause GABA to have a greater effect at a lower
dose.
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Allosteric site

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Intrinsic activity: This is a measure of the
ability of an agonist to induce a response
by the receptors. It is defined as the
maximum response to the test agonist
relative to the maximum response to a
full agonist acting on the same
receptors. All full agonists, by definition,
have an intrinsic activity of 1 whereas
partial agonists have an intrinsic activity
of less than 1.
• Efficacy (e): This is a measure of the
inherent ability of an agonist to initiate a
physiological response following binding
to the orthostatic site. The initiation of a
response is linked to the ability of the
agonist to promote the formation of the
active conformation of the receptors
whereas for inverse agonists it is linked
to their ability to promote the formation
of the inactive conformation. While all
full agonists must have a high efficacy
their efficacy values will not necessarily
be equal, in fact values of have no
theoretical maximum value. Partial
agonists have a low efficacy, antagonists
have zero efficacy and inverse agonists
have negative efficacy.

12. • Two-State Model:-
• The two step model can provide a simple approach, the
occupied receptor can switch from its resting state to an
activated (R*)state, R* being favoured by binding of an
agonist but not an antagonist molecule. Receptor exist in
this two conformational states. When no ligand is present
the equilibrium lies far to left. Agonist have higher affinity
towards R* wrt to R. The greater the relative affinity for R*
the greater is the efficacy of the agonist.
• An inverse agonist has higher affinity for the R than R* state
and so shift the equilibrium to the left.
• A neutral antagonist has equal affinity for both the state so
does not by itself affect the conformation.
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13. r R
Agonist
rA R*A
Inverse
Agonist
active
inactive
Partial agonists and antagonists
bind to both r and R states
Receptor states and inverse agonists
Activation in the absence of an agonist; over-expression
(Two-State Model)

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Energy landscape diagram describing a possible
mechanism of GPCR activation by an agonist

15. • Biased Agonism:-
• A major problem with the two-state model is that as we
know receptor are not actually restricted to two distinct
states but have a much greater conformational flexibility ,so
there is more than one inactive and active form . The different
conformation that they can adopt may be preferentially
stabilised by different ligands and may produce different
functional effects by activating different signal transduction
pathways.
• Receptor that coupled to second messenger system can
couple to more than one intracellular effectors pathway
giving rise to two or more simultaneous responses. Different
agonist can exhibit bias for the generation of one response
over another even although they are acting via same receptor.
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Kappa opioid receptor (κ-OR) agonists are promising therapeutic candidates for
pain and itch; however, they also exhibit the adverse effects of sedation and
dysphoria. A recent study has demonstrated that a G protein-biased agonist for
κ-OR provides effective pain and itch relief without causing sedation or
dysphoria.

18. • Inverse Agonist:-
• Many receptor exhibit some constitutive activity in the
absence of regulatory ligands, drugs that stabilize such
receptor in inactive conformation termed as inverse agonist
For example, it may be that benzodiazepines are agonists at
GABA receptors expressing intrinsic efficacy as the degree of
allosteric perturbation induced to the receptor to alter GABA
binding. Alternatively, differential binding to multiple
conformational states of the receptor may reflect intrinsic
efficacy3.
• Efficacy = -1
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19. • Partial Agonist :-
• The ability of a drug molecule to activate the receptor is
actually a graded, rather than an all or noting phenomenon.
If a series of chemically related agonist drugs acting on the
same receptor is tested on a given biological system ,it is
often found that the largest response can differ from one
drug to another.
• These ligands partially increases the activity of the receptor.
Partial agonists produce a maximal response which is below
the maximum for that tissue (as define by a full agonist)1.
• A partial agonist has lower efficacy such that 100%
occupancy results only sub maximal effect.
• Example include buprenorphine in management of severe
pain.
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21. • PARTIAL AGONISTS CAN TRIGGER WITHDRAWAL:-
• Apparently mu receptors have more affinity for partial
agonists like buprenorphine than they have for full
agonists. For example, if someone has been taking a
full agonist like OxyContin and there is still some active
OxyContin in their body, taking a partial agonist like
buprenorphine causes the mu receptors to accept the
partial agonist and this prevents the full agonists from
reaching the mu receptors. If the full agonist was still
stimulating some of the receptors before the introduction of
the partial agonist and causing our elevator to rise to the
eighth floor, then by blocking the access to the mu
receptors, the buprenorphine only allows the elevator to rise
to the fourth floor and this can cause immediate withdrawal
symptoms.
• This effect is increased because buprenorphine is slower
acting than many other opioids and remains in the
mu receptor blocking it for a longer period of time.
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• COMPARING EFFECTS OF FULL AGONIST AND PARTIAL AGONIST
• Each time a person takes a full agonist it contains a code,
unless significantly modified by the DNA and the way the
full agonist is metabolized, which will allow the elevator to
reach a certain floor. In low doses, the elevator code
(number of endorphins created) may only allow the elevator
to reach the second floor. However, as the
full agonist dosage increases, the elevator code can now rise
to higher floors and eventually to the tenth floor.
• A partial agonist, like buprenorphine, will only stimulate the
mu receptors to produce a certain amount of
endorphins. Using our elevator example, when an
individual takes a partial agonist in small doses it may
contain a code that allows the elevator to rise to the second
floor. However, no matter how much the dosage of the
partial agonist increases, the code in the partial agonist will
not allow the elevator to rise above the fourth floor.
• This is why it is much harder to abuse a partial agonist than
a full agonist. The partial agonist has a lower intrinsic
activity than full agonist5.

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24. • Reference:-
1 Goodman and Gilman’s The pharmacological basis of
therapeutics, 12th edition vol 278 p:42-50
2 Wood, P. L., Loo, P., Braunwalder, A.,Yokoyama, N. and Cheney,
D. L. (1984) J. Pharmacol. Exp. Ther. 231, 572-576
3 Karlin, A. (1967) J. Theoret. Biol. 16, 306-320
4 Rang & Dale’s Pharmacology, 8th edition p:10-20
5 http://effectivediagnosis.org/full-agonists-partial-agonists-
antagonists/
6 Ji, T. H., Grossmann, M., and Ji, I. (1998) J. Biol. Chem. 273,
17299–17302
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