Identification of allosteric antagonists of receptor-guanine nucleotide-binding protein interactions.

A series of compounds that inhibit the coupling of the alpha 2-adrenergic receptor and the beta 2-adrenergic receptor to the guanine nucleotide-binding proteins (G proteins) Gi and Gs, respectively, have been identified. This inhibition of G protein coupling was detected by the ability of the compounds to reduce the affinity of these receptors for agonists without affecting antagonist affinity. Analysis of the structure-activity relationships of these compounds revealed a requirement for regularly spaced anionic substituents on amphipathic structures for this inhibition to occur. The compounds do not interact at the ligand binding site of the receptor or at the GTP binding site of the G protein. The identification of compounds that can uncouple receptors from G proteins demonstrates the potential for the discovery of small molecule inhibitors of receptor-G protein interactions that act as allosteric antagonists at this site.