Intrinsic activity
This article needs attention from an expert in pharmacology. The specific problem is: There are mistakes in this article; efficacy and intrinsic activity are different properties.(April 2019) |
Intrinsic activity (IA) and efficacy refer to the relative ability of a
Mechanism of efficacy
Ligand | Description | % Efficacy (E) | ||||
---|---|---|---|---|---|---|
Superagonist | Efficacy higher than the endogenous agonist | E | > | 100 | ||
Full agonist
|
Efficacy equal to the endogenous agonist | E | = | 100 | ||
Partial agonist | Efficacy less than the endogenous agonist | 0 | < | E | < | 100 |
Silent antagonist | Affinity but no efficacy | E | = | 0 | ||
Inverse agonist | Inverse efficacy | E | < | 0 |
Agonists of lower efficacy are not as efficient at producing a response from the drug-bound receptor, by stabilizing the active form of the drug-bound receptor. Therefore, they may not be able to produce the same maximal response, even when they occupy the entire receptor population, as the efficiency of transformation of the inactive form of the drug-receptor complex to the active drug-receptor complex may not be high enough to evoke a maximal response. Since the observed response may be less than maximal in systems with no spare receptor reserve, some low efficacy agonists are referred to as partial agonists.[2] However, it is worth bearing in mind that these terms are relative - even partial agonists may appear as full agonists in a different system/experimental setup, as when the number of receptors increases, there may be enough drug-receptor complexes for a maximum response to be produced, even with individually low efficacy of transducing the response. There are actually relatively few true full agonists or silent antagonists; many compounds usually considered to be full agonists (such as DOI) are more accurately described as high efficacy partial agonists, as a partial agonist with efficacy over ≈80-90% is indistinguishable from a full agonist in most assays. Similarly many antagonists (such as naloxone) are in fact partial agonists or inverse agonists, but with very low efficacy (less than 10%). Compounds considered partial agonists tend to have efficacy in between this range. Another case is represented by silent agonists,[3] which are ligands that can place a receptor, typically an ion channel, into a desensitized state with little or no apparent activation of it, forming a complex that can subsequently generate currents when treated with an allosteric modulator.[4]
Intrinsic activity
Intrinsic activity of a test agonist is defined as:
- [5]: 24
Stevenson's efficacy
R. P. Stephenson (1925–2004) was a British pharmacologist.[6] Efficacy has historically been treated as a proportionality constant between the binding of the drug and the generation of the biological response.[7] Stephenson defined efficacy as:
- [5]: 25
where is the proportion of agonist-bound receptors (given by the Hill equation) and is the stimulus to the biological system.[8] The response is generated by an unknown function , which is assumed to be
Furchgott's efficacy
Robert F. Furchgott later improved on Stephenson's model with the definition of efficacy, e, as
where is the intrinsic efficacy and is the total concentration of receptors.
Stevenson and Furchgott's models of efficacy have been criticised and many more have been developed. The models of efficacy are shown in Bindslev (2008).[9][10]
References
- PMID 13383117.
- ^ "In vitro pharmacology: concentration-response curves". Glaxo Wellcome pharmacology guide. Retrieved 2009-07-11.
- PMID 23746476.
- PMID 28494140.
- ^ ISBN 9781439887578.
- ^ "R P ('Steve') Stephenson". Pharmacology Hall of Fame. British Pharmacological Society. 2 June 2016.
- ^ Brunton L, Chabner BA, Knollman B (2011). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). p. 46.
- ^ ISBN 978-3-540-66124-5.
- ISBN 978-91-977071-0-7.
- S2CID 83584731.