Allosteric modulation of G protein-coupled receptors.

: Allosteric modulation of G protein-coupled receptors has recently been recognized as an alternative approach for selectivity in drug action. Allosteric modulators that enhance or diminish the effects of (endogenous) agonists or antagonists on a variety of G protein-coupled receptors are described in this review, with emphasis on the latest developments in this research area. Specific examples include allosteric ligands for adenosine A1 and A3 receptors, Ca(2+)-sensing receptors, metabotropic glutamate receptor subtypes, gamma-aminobutyric acid type B and muscarinic receptors. It appears that all three major classes of G protein-coupled receptors (A, B and C) are amenable to allosteric modulation by small molecules. This constitutes an attractive and novel means to identify new leads in the drug discovery process. However, it requires a reengineering of most current assays.