Intrinsic activity

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Efficacy spectrum of receptor ligands.

Intrinsic activity (IA) or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the potency of the drug and which is proportional to both efficacy and affinity. This use of the word "efficacy" was introduced by Stephenson (1956)[1] to describe the way in which agonists vary in the response they produce, even when they occupy the same number of receptors. High efficacy agonists can produce the maximal response of the receptor system while occupying a relatively low proportion of the receptors in that system.

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.

Ligand Description  % Efficacy (E)
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

References[edit]

  1. ^ Stephenson RP (December 1956). "A modification of receptor theory". Br J Pharmacol Chemother 11 (4): 379–93. doi:10.1111/j.1476-5381.1956.tb00006.x. PMC 1510558. PMID 13383117. 
  2. ^ "In vitro pharmacology: concentration-response curves". Glaxo Wellcome pharmacology guide. Retrieved 2009-07-11.