Allosteric modulator

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In biochemistry and pharmacology, an allosteric modulator (allo- from the Greek meaning "other") is a substance which indirectly influences (modulates) the effects of a primary ligand that directly activates or deactivates the function of a target protein. Targets may be metabotropic, ionotropic and nuclear receptors, enzymes and transporters[1].

The principal binding site of a macromolecule is termed the 'orthosteric site'. An example is the active site on an enzyme, where a substrate binds. Though, in addition to the orthosteric site, some macromolecules can have their activity affected by ligands binding at a second, 'allosteric' binding site, distinct from the orthosteric site. Allosteric modulators stabilize a conformation of the protein structure that affects either the binding or the efficacy of the primary ligand. Pure modulators have no direct effect on the function of the protein target. The modulatory properties are interdependent with the ternary complex consisting of the target protein, the primary ligand and the modulator.

Types of allosteric modulator[edit]

Positive allosteric modulators (PAMs), also known as allosteric enhancers or potentiators, induce an amplification of the effect of receptor's response to the primary ligand without directly activating the receptor.[2][3] Benzodiazepines principally act as PAMs at the GABAA receptor.[4]

Negative allosteric modulators (NAMs) act at an allosteric site to reduce the responsiveness of the receptor to the endogenous ligand.[3] Ro15-4513 is a NAM at the α1β2γ2 GABAA receptor[citation needed].[nb 1]

Silent allosteric modulators (SAMs), also called neutral or null modulators, occupy the allosteric binding site and behave functionally neutral. Flumazenil can be regarded as such an example.

The modulatory activity can be first-order, second-order, or both. Second-order modulators alter the modulatory activity of first-order modulators, whereas first-order modulators do not alter the activity of other allosteric modulators.[citation needed] (−)‐Epigallocatechin‐3‐gallate is one such example of a second-order modulator at GABAA receptors.[6]

Allosteric agonists[edit]

Allosteric agonists are to be distinguished from pure allosteric modulators. They are defined as ligands able to directly activate a receptor by binding to an allosteric agonist binding site distinct from the primary (orthosteric) site. They are able to exert their effect in the absence of an orthosteric ligand. Allosteric ligands may also possess antagonistic and inverse agonistic properties analogously to orthosteric ligands.

Ago-allosteric modulators[edit]

Ago-allosteric modulators are both allosteric agonists and allosteric modulators. An ago-allosteric modulator acts as an agonist and an enhancer for endogenous agonists in increasing agonist potency (the dose range over which a response is produced) and providing "superagonism". Superagonism results when the efficacy is greater than 100 percent. Ago-allosteric modulators can be neutral, negative, or positive. Neutral ago-allosteric modulators increase efficacy, but have no effect on potency. A negative ago-allosteric modulator has a negative effect on the potency but a positive effect on the efficacy of an agonist. A positive ago-allosteric modulator increases both efficacy and potency.

See also[edit]

Notes[edit]

  1. ^ Ro15-4513 is also a PAM at α6β2γ2.[5]

References[edit]

  1. ^ Rothman RB, Ananthan S, Partilla JS, Saini SK, Moukha-Chafiq O, Pathak V, Baumann MH (June 2015). "Studies of the biogenic amine transporters 15. Identification of novel allosteric dopamine transporter ligands with nanomolar potency". J. Pharmacol. Exp. Ther. 353 (3): 529–38. doi:10.1124/jpet.114.222299. PMC 4429677. PMID 25788711.
  2. ^ May, Lauren T.; Leach, Katie; Sexton, Patrick M.; Christopoulos, Arthur (2007). "Allosteric Modulation of G Protein–Coupled Receptors". Annual Review of Pharmacology and Toxicology. 47 (1): 1–51. doi:10.1146/annurev.pharmtox.47.120505.105159. PMID 17009927.
  3. ^ a b Goodman and Gilman. (2011). The Pharmacological Basis of Therapeutics. 12th ed. p. 220
  4. ^ Olsen RW, Betz H (2006). "GABA and glycine". In Siegel GJ, Albers RW, Brady S, Price DD (eds.). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (7th ed.). Elsevier. pp. 291–302. ISBN 978-0-12-088397-4.
  5. ^ Knoflach, F; Benke, D; Wang, Y (1996). "Pharmacological modulation of the diazepam-insensitive recombinant gamma-aminobutyric acidA receptors alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2". Molecular Pharmacology.
  6. ^ Campbell, EL; Chebib, M; Johnston, GAR (2004). "The dietary flavonoids apigenin and (−)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABAA receptors". Biochemical Pharmacology. 68 (8): 1631–8. doi:10.1016/j.bcp.2004.07.022. PMID 15451406.


  • J. Monod; J. Wyman; J.P. Changeux (1965). "On the nature of allosteric transitions: A plausible model". Journal of Molecular Biology. 12 (1): 88–118. doi:10.1016/S0022-2836(65)80285-6. PMID 14343300.
  • T.W. Schwartz; B. Holst (2006). "Ago-allosteric modulation and other types of allostery in dimeric 7TM receptors". Journal of Receptors and Signal Transduction Research. 26 (1): 88–118.
  • Schwartz, Thue W.; Birgitte Holst. (2007). "Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?". Trends in Pharmacological Sciences. 28 (8): 366–373. doi:10.1016/j.tips.2007.06.008. PMID 17629958.