Medicinal chemistry and molecular pharmacology of GABA receptors and glutamate transporters - Complementary structure-activity relationships

GABA and glutamate are the major inhibitory and excitatory neurotransmitter s, respectively, in the human brain. Many GABA and glutamate receptors and transporters are key protein targets for drug development, and many known C NS drugs act on these targets. There have been a substantial number of trad itional studies of structure-activity relationships in this area. The adven t of modern molecular biology using recombinant DNA technology enables stud ies of structure-activity relationships to be carried out on these protein targets, thus complementing structure-activity relationships for the ligand s interacting with these targets. This is illustrated with examples from ou r investigations of subtypes of GABA(C) receptors and glutamate transporter s using both native and chimeric proteins of known amino acid sequence expr essed in Xenopus oocytes. Studies of such complementary structure-activity relationships involving structural variations of both the ligands and their targets will play important roles in drug development. Such studies are vi tal to the development of drugs that interact selectively with particular n ative and mutant protein receptor/transporter subtypes. Drug Dev. Res. 46:2 55-260, 1999. (C) 1999 Wiley-Liss, Inc.