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Chapter 3. Metabotropic Glutamate Receptors: Agonists, Antagonists and

Alfosteric Modulators

Corinne E. Augelli-Szafran and Roy D. Schwarz Pfizer Global Research & Development Ann Arbor Laboratories 2800 Plymouth Road, Ann Arbor, Ml 48105

Introduction - The excitatory neurotransmitter glutamate acts at a variety of receptors in both the central and peripheral nervous systems, and these sites are broadly divided into two major types, lonotropic glutamate receptors (iGluRs) are contained within ligand gated-ion channel complexes and include NMDA, AMPA, and kainate receptor subtypes with each subtype possessing a distinct pharmacology (1, 2). Metabotropic glutamate receptors (mGluRs) are members of the super family of G-protein coupled receptors (GPCRs) and the eight subtypes (mGluRs 1-8) are divided into three Groups/Families based upon sequence homology, common signal transduction mechanisms, and pharmacology. Group I receptors (mGluRs 1 and 5) couple to Gq and activate phospholipase C, while Group II receptors (mGluRs 2 and 3) and Group III receptors (mGluRs 4, 6, 7, and 8) couple to Gi/Go and result in the inhibition of cAMP formation. In general, it appears that Group I receptors are often located presynaptically and upon activation increase excitability, while Groups ll/lll have a greater postsynaptic localization and dampen excitability (3,4).

Early development of mGluR pharmacological agents focused predominantly on synthesizing amino acid-like structures that, in general, yielded relatively weak compounds (by today's standards) that often had activity at multiple subtypes and in some cases showed agonist activity at one receptor and antagonist activity at others (5). Subsequent chemistry focusing on specific subtypes created non-amino acid subtype selective compounds with low nanomolar affinity (6). Other reports in the literature have now shown that potent agonists and antagonists have been identified for many (but still not all) of the subtypes and that there are also positive and negative allosteric modulators of mGluR receptor function (7, 8). The purpose of this report is to provide an update on the pharmacology of mGluR receptors since the last review with an emphasis on selective ligands and allosteric modulators (6).

Like other members of Family/Type 3 GPCRs (which include GABA-B receptors, Ca++-sensing receptors and pheromone receptors), mGluRs have a large amino terminal domain (ATD) that contains the recognition site for the endogenous ligand, which in this case is glutamate (9-11). There appears to be homology with bacterial periplasmic binding proteins that suggests the ATD is composed of two large globular domains linked by a hinge region. These domains exist in equilibrium between an open (inactive) and a closed (active) form with the overall confirmation altered by agonist binding (12). Additionally, there are sites within the seven transmembrane-spanning domains, which bind a variety of agents that either positively or negatively modulate responses produced by glutamate receptor activation. These sites present novel targets for drug discovery and are now being actively pursued (13-15).

Agonists and Positive Allosteric Modulators - A limited number of mGluRI agonists and positive allosteric modulators have been identified recently. Various amido analogs such as 1 and 2 through 4 have been disclosed as mGluRI agonists over the past few years (16-21). Compound I showed an IC5o value of 20 nM in a receptor binding assay and was suggested to be of use in the prevention and treatment of cerebral infarction.

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