Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?

Trends Pharmacol Sci. 2007 Aug;28(8):366-73. doi: 10.1016/ Epub 2007 Jul 13.


Many small-molecule agonists also display allosteric properties. Such ago-allosteric modulators act as co-agonists, providing additive efficacy--instead of partial antagonism--and they can affect--and often improve--the potency of the endogenous agonist. Surprisingly, the apparent binding sites of several ordinary allosteric enhancers and ago-allosteric modulators seem to overlap with those of the endogenous agonists. Different molecular scenarios are proposed to explain this discrepancy from classical allosteric models. In one scenario, the ago-allosteric modulator can interchange between different binding modes. In another, dimeric, receptor scenario, the endogenous agonist binds to one protomer while the ago-allosteric modulator binds to the other, 'allosteric' protomer. It is suggested that testing for ago-allosteric properties should be an integral part of the agonist drug discovery process because a compound that acts with--rather than against--the endogenous agonist could be an optimal agonist drug.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Allosteric Regulation
  • Binding Sites
  • Humans
  • Ligands
  • Models, Biological
  • Pharmaceutical Preparations / chemistry*
  • Pharmaceutical Preparations / metabolism*
  • Protein Binding
  • Receptors, GABA / chemistry
  • Receptors, GABA / metabolism
  • gamma-Aminobutyric Acid / chemistry
  • gamma-Aminobutyric Acid / metabolism


  • Ligands
  • Pharmaceutical Preparations
  • Receptors, GABA
  • gamma-Aminobutyric Acid