Medicinal Chemistry and Molecular Pharmacology of GABA Receptors and Glutamate Transporters— Complementary Structure–Activity Relationships

GABA and glutamate are the major inhibitory and excitatory neurotransmitters, respectively, in the human brain. Many GABA and glutamate receptors and transporters are key protein targets for drug development, and many known CNS drugs act on these targets. There have been a substantial number of traditional studies of structure–activity relationships in this area. The advent of modern molecular biology using recombinant DNA technology enables studies of structure–activity relationships to be carried out on these protein targets, thus complementing structure–activity relationships for the ligands interacting with these targets. This is illustrated with examples from our investigations of subtypes of GABAC receptors and glutamate transporters using both native and chimeric proteins of known amino acid sequence expressed 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 vital to the development of drugs that interact selectively with particular native and mutant protein receptor/transporter subtypes. Drug Dev. Res. 46:255–260, 1999. © 1999 Wiley-Liss, Inc.