Agonists and Antagonists for Metabotropic Glutamate Receptors

Abstract

<p>Glutamate (Glu) is a prominent excitatory amino acid (EAA) neurotransmitter in the central nervous system, and it exerts its actions at a number of different receptor subclasses. lonotropic Glu receptors, such as the N-methyl-D-aspartate (NMDA), 2- amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid (AMPA), and kainic acid subtypes, are coupled to ion channels, and transduce signals by gating the flow of calcium and sodium ions into the cell. Metabotropic EAA receptors (mGluRs) are coupled through G-proteins to intracellular enzymes such as phospholipase C (PLC) and adenylate cyclase (AC). Agonist activation of mG!uRs coupled to PLC produces an increase in the intracellular concentrations of inositol triphosphate (IP3) and diacylglycerol (DAG), while agonist activation of mG!uRs coupled to AC produces a decrease in intracellular concentrations of cyclic­ adenosine monophosphate (cAMP). At least eight distinct metabotropic receptor proteins (mGluRl-8) have been identified, and these can be divided into three groups. Group 1 mG!uRs consist of mG!uRl and mG!uR5, and are PLC-coupled receptors. Group 2 mG!uRs include mG!uR2 and mG!uR3, and are negatively coupled to AC. </p><p> Group 3 mG!uRs consist of mGluR4, mG!uR6, mGluR 7and mGluR8, and they are also negatively coupled to AC. Many studies are currently underway to identify novel agonists and antagonists for these receptors. The discovery of such compounds will be an important step toward understanding the physiological and pathophysiological consequences of mG!uR activation in vivo, and will ultimately be essential in defining the therapeutic potential of selective mGluR agents. Novel aspects of the medicinal chemistry and pharmacology of metabotropic receptors are discussed in this review.