DRUGS INTERACTING WITH G-PROTEIN ALPHA-SUBUNITS - SELECTIVITY AND PERSPECTIVES

Extracellular signal molecules as diverse as hormones, neurotransmitte rs and photons use a signal transduction pathway involving a receptor, a G protein and effecters. Compounds that interact directly with G pr oteins can mimic the receptor-G protein interaction or can block the a ctivation of G proteins by receptors. Several binding sites exist on t he G(alpha) protein that may be exploited for the design of synthetic stimulatory or inhibitory ligands. The effector binding site is regula ted by endogenous proteins and appears to be a target for selective ex ogenous ligands. The GTP binding site presents a large homology within the G protein families and therefore the nucleotide analogs might not be considered as a tool to discriminate between the G protein subclas ses. In contrast, different experimental strategies have substantiated the specificity in the interaction between a receptor and a G protein , the receptor binding site of G proteins should be considered as pote ntial drug targets. Drugs interfering with this site such as mastopara n and related peptides, GPAnt-2 and suramin, are lead compounds in the design of selective G protein antagonists. Benzalkonium chloride and methoctramine have agonist or antagonist properties, depending on G pr otein subtypes. Such compounds would be very useful to delineate the f unctions of G proteins and G protein-coupled receptors, to understand some side effects of drugs used in therapy and to develop new therapeu tic agents. (C) 1998 Elsevier, Paris.