Agonists, partial agonists,

Introduction To general pharmacology.

1. Agonists, Partial agonists, and I nverse agonists Name -Jayita Das 18PCM2785 Department – Pharmacology and toxicology 1

2. Content:- Pharmacodynamic concept Drug Ligand Receptor interaction Two state model Biased Agonism Agonist Partial agonist Inverse agonist Reference 2

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. 3

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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 8

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. 9 Allosteric site

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11. 11 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 Mode l:- 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. 12

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 R R*A (Two-State Model)

14. 14 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. 15

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17. 17 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 efficacy 3 . Efficacy = -1 18

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. 19

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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 .  21

22. 22 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 agonist 5 .

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24. Reference:- 1 Goodman and Gilman’s The pharmacological basis of therapeutics, 12 th 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 Karlin , A. (1967) J. Theoret. Biol. 16, 306- 320 Rang & Dale’s Pharmacology, 8 th edition p:10-20 http://effectivediagnosis.org/full-agonists-partial-agonists-antagonists/ Ji , T. H., Grossmann, M., and Ji , I. (1998) J. Biol. Chem. 273, 17299–17302 24

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