Allosteric modulators, which act by modulating the effects of endogenous agonists rather than by directly activating or blocking receptors, can have distinct advantages as therapeutic agents, including high selectivity and large safety margins. Modulation has been observed in a number of receptor systems, the best characterized being the GABA A receptor (GABA AR), which is modulated by benzodiazepines, barbiturates, steroids, and certain metal cations. Unfortunately, modulation is not well understood, and the lack of a theoretical model of receptor modulation is an obstacle to rational design of modulators. The overall goal of this project is to understand the mechanisms whereby drugs can modulate receptor function, and thereby to establish a sound theoretical basis for the rational design of allosteric modulators. Toward this end, a mathematical theory of receptor modulation has been developed. This proposal aims to test that theory, using the GABA AR as a model system. An important prediction of the model is that the effects of a modulator upon the agonist dose-response relationship will be dependent upon the efficacy of the particular agonist used. To test the model, a series of GABA AR agonists will be characterized electrophysiologically as to relative efficacy and potency, and the effects of GABA AR modulators upon agonist dose-response curves will be compared to the predictions of the model. In addition to confirming or rejecting the theoretical model, these studies are expected to yield novel data regarding GABA AR agonist efficacy. Conventional pharmacological methods of receptor characterization, which rely principally upon differences in potency, have been largely inadequate to deal with the multiplicity of GABA AR subtypes in the central nervous system. It is likely that agonist efficacy will be highly sensitive to subtle differences in receptor structure. A second goal of this proposal is therefore to develop a more powerful strategy for pharmacological characterization of GABA AR subtypes, by exploiting differences in agonist efficacy as well as potency. It is anticipated that this general approach will be broadly applicable to the study of other neurotransmitter receptors in the central nervous system.
| Downing, Scott S; Lee, Yan T; Farb, David H et al. (2005) Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABA(A) receptors supports an allosteric model of modulation. Br J Pharmacol 145:894-906 |
