Intrinsic activity

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.{{cite web | url = http://www.pdg.cnb.uam.es/cursos/Barcelona2002/pages/Farmac/Comput_Lab/Guia_Glaxo/chap2c.html | title = In vitro pharmacology: concentration-response curves | work = Glaxo Wellcome pharmacology guide | access-date = 2009-07-11 | archive-date = 2019-07-26 | archive-url = https://web.archive.org/web/20190726074523/http://www.pdg.cnb.uam.es/cursos/Barcelona2002/pages/Farmac/Comput_Lab/Guia_Glaxo/chap2c.html | url-status = dead }} 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,{{cite journal | vauthors = Chojnacka K, Papke RL, Horenstein NA | title = Synthesis and evaluation of a conditionally-silent agonist for the α7 nicotinic acetylcholine receptor | journal = Bioorganic & Medicinal Chemistry Letters | volume = 23 | issue = 14 | pages = 4145–4149 | date = July 2013 | pmid = 23746476 | pmc = 3882203 | doi = 10.1016/j.bmcl.2013.05.039 }} 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.{{cite journal | vauthors = Quadri M, Matera C, Silnović A, Pismataro MC, Horenstein NA, Stokes C, Papke RL, Dallanoce C | display-authors = 6 | title = Identification of α7 Nicotinic Acetylcholine Receptor Silent Agonists Based on the Spirocyclic Quinuclidine-Δ² -Isoxazoline Scaffold: Synthesis and Electrophysiological Evaluation | journal = ChemMedChem | volume = 12 | issue = 16 | pages = 1335–1348 | date = August 2017 | pmid = 28494140 | pmc = 5573630 | doi = 10.1002/cmdc.201700162 }}

Intrinsic activity of a test agonist is defined as:

:$\backslash mathrm\{IA\}=\backslash frac\{\backslash text\{maximal\; response\; to\; the\; test\; agonist\}\}\{\backslash text\{maximal\; response\; to\; full\; agonist\}\}${{r|Foreman|p=24}}

R. P. Stephenson (1925–2004) was a British pharmacologist.{{cite web|url=https://www.bps.ac.uk/about/about-pharmacology/pharmacology-hall-of-fame/articles/r-p-(-steve-)-stephenson | date = 2 June 2016 | work = Pharmacology Hall of Fame | publisher = British Pharmacological Society | title = R P ('Steve') Stephenson}} Efficacy has historically been treated as a proportionality constant between the binding of the drug and the generation of the biological response.{{cite book|title=Goodman and Gilman's The Pharmacological Basis of Therapeutics |edition=12th |page= 46|title-link=Goodman %26 Gilman%27s The Pharmacological Basis of Therapeutics|year=2011| vauthors = Brunton L, Chabner BA, Knollman B }} Stephenson defined efficacy as:

:$S=ep${{cite book|url=https://books.google.com/books?id=Y9bsUpefYW0C&pg=PA51|title=Textbook of Receptor Pharmacology | edition = Second | vauthors = Foreman JC, Johansen T, Gibb AJ |publisher=CRC Press|year=2009|isbn=9781439887578 }}{{rp|25}}

where $p$ is the proportion of agonist-bound receptors (given by the Hill equation) and $S$ is the stimulus to the biological system.{{cite book | vauthors = Linderman JJ | chapter = Kinetic Modeling Approaches to Understanding Ligand Efficacy | veditors = Kenakin T, Angus JA |title=The Pharmacology of Functional, Biochemical, and Recombinant Receptor Systems |date=2000 |publisher=Springer |location=Berlin |isbn=978-3-540-66124-5 |page=120}} The response is generated by an unknown function $f(S)$, which is assumed to be hyperbolic. This model was arguably flawed in that it did not incorporate the equilibrium between the inactivated agonist-bound-receptor and the activated agonist-bound-receptor that is shown in the del Castillo Katz model.

Robert F. Furchgott later improved on Stephenson's model with the definition of efficacy, e, as

:$S=\backslash underbrace\{\backslash varepsilon[\backslash ce\{R\}]\_\{\backslash mathrm\{Tot\}\}\}\_\{e\}\backslash cdot\; p$

where $\backslash varepsilon$ is the intrinsic efficacy and $[\backslash ce\{R\}]\_\{\backslash mathrm\{Tot\}\}$ 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).{{cite book|vauthors=Bindslev N|title=Drug-Acceptor Interactions: Modeling Theoretical Tools to Test and Evaluate Experimental Equilibrium Effects|chapter=Chapter 1: Simple Agonism|pages=19–20|isbn=978-91-977071-0-7|doi=10.4324/9781315159782|doi-access=free|year=2008|publisher=CRC Press|location=London}}{{cite journal | vauthors = Kirkeby H|title=Drug–Acceptor Interactions–Modeling theoretical tools to test and evaluate experimental equilibrium effects (Book review)|journal=Microbial Ecology in Health and Disease |date=2017 |volume=20 |issue=4 |page=213 |publisher=Routledge |location=London |isbn=978-1-351-66057-0 | doi = 10.1080/08910600802431931 |s2cid=83584731 |doi-access=free }}

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{{Pharmacology}}

{{Receptor agonists and antagonists}}

Category:Pharmacodynamics