Allosteric Modulators: The New Generation Of Gaba(B) Receptor Ligands

Allosteric modulators are molecules that interact with a site on a receptor which is distinct from the orthosteric recognition site for the endogenous ligand. By modifying the receptor conformation, they change the affinity and/or efficacy of agonists, but often have no intrinsic activity on their own. Because of this use-dependent mechanism, they are expected to have a much better side-effect profile than agonist drugs. The first positive GABA type B (GABA(B)) receptor modulators, CGP7930 and GS39783, have been described more than 10 years ago. They were discovered in a high-throughput screen using GTP(gamma)S-35 assays, in which they enhanced both the affinity and the maximal effect of gamma-aminobutyric acid (GABA), without having any agonist activity of their own. This positive modulation was subsequently confirmed in a number of different radioligand binding, biochemical and electrophysiological assay systems. The recombinant expression of engineered receptor constructs allowed to locate the site of action of these positive modulators to the seven-transmembrane domain of the GABA(B2) subunit, through which they could to some extent directly activate the receptor in sufficiently sensitive assay systems. These early findings have fostered the search for other molecules acting in a similar way, and a number of positive GABA(B) receptor modulators, and also the first negative modulators, have been described in recent years. In vivo microdialysis experiments have demonstrated at the biochemical level that the mechanism of positive allosteric GABA(B) receptor modulation also applies in living animals. Behavioural experiments have confirmed that positive GABA(B) receptor modulators have a better side-effect profile than the therapeutically used agonist drug baclofen. Numerous studies have shown that these compounds show promising activity in animal models for anxiety, drug and alcohol abuse, pain, gastrointestinal indications and possibly more.