Current Topics in Medicinal Chemistry - Volume 5, Issue 9, 2005

Glutamate (glutamic acid) is the major excitatory neurotransmitter in the mammalian CNS, exterting its modulatory effects through either ionotropic or metabotropic glutamate receptors (mGluRs). The mGluRs are family C G-protein coupled receptors, characterized by a large extracellular amino-terminal agonist binding site. Eight mGluRs have been cloned, sequenced and assigned to three groups based on their structure, coupling to effector mechanisms and pharmacology. Group I mGluRs (mGluR1 and mGluR5) are postsynaptic receptors while Group II (mGluR2 and mGluR3) and Group III (mGluR6, mGluR7 and mGluR8) are located presynaptically. Dysfunction in glutaminergic systems has been implicated in a number of neurological and psychiatric disorders including pain, addiction, Parkinson's disease, anxiety and schizophrenia. Recent studies suggest that small molecules capable of modulating mGluR activity will have broad applicability for the treatment of a variety of CNS pathologies. This issue contains a collection of reviews covering cutting-edge biology and medicinal chemistry for all 8 mGluR subtypes as well as a general introduction to this nacsent field. Importantly, the reviews describe the discovery and development of selective agonists, antagonists and allosteric modulators (both positive and negative) that target individual mGluR subtypes. The authors have included background biology relevant to understanding the target(s) for therapeutic intervention, lead discovery and progress towards target validation in various electrophysiological and animal behavioral models. I would like to thank the authors for their hard work, dedication and excellent, comprehensive contributions to this special issue of Currents Topics in Medicinal Chemistry. Our hope is that this issue will serve as a key reference work for those engaged in, or interested in, metabotropic gluatmate receptors and the various strategies employed to modulate this class of GPCRs for a number of therapeutic implications.

This review provides an overview of the drug discovery process used to identify, develop and characterize the first positive allosteric modulators of the metabotropic glutamate receptor (mGluR) subtype 5 (mGluR5). Discovery and optimization of three series of positive allosteric modulators are described, each using different approaches. The symmetric benzaldazine series was discovered and optimized from samples already existing in our sample collection without an active synthetic program to further elucidate SAR. This series yielded a family of highly selective pharmacological tools that produced positive, negative and neutral allosteric modulation of mGluR5 activity. The original compound in the benzamide series was discovered from screening and this series was optimized using an iterative library synthesis approach to explore SAR in each of three regions of the molecule. This series produced more potent positive allosteric mGluR5 modulators than the benzaldazine series which could be evaluated for their effect on mGluR5 in brain slice electrophysiological studies. The pyrazole series used a fragment library approach based on small structural motives from the benzamide series to discover lead compounds and establish SAR. This series produced still more potent positive allosteric mGluR5 modulators with improved pharmacokinetic and physical properties. These modulators showed efficacy in animal behavioral models in which other antipsychotic drugs were active. Evaluation of assay data in mathematical models of allosterism to constrain possible mechanisms of action is briefly discussed. Other reviews of this emerging field with different emphases have been published recently [1-3].

Our understanding of glutamatergic transmission in the central nervous system has been greatly expanded with the discovery and investigation of the metabotropic glutamate receptor family. Complementing the ionotropic glutamategated ion channels, these G-protein coupled receptors play critical roles in neuronal and glial functions such as the modulation of neuronal excitability, synaptic transmission, and various metabolic functions. Because of the ubiquitous distribution of glutamatergic synapses, it has been deemed likely that mGlu receptors participate in most, if not all, major functions of the CNS. It is predicted that the wide diversity and heterogeneous distribution of mGlu receptor subtypes will provide avenues to develop clinically relevant pharmacological agents that target specific CNS systems. mGlu receptors are regulated by differences in expression, alternative splicing patterns, and interactions with other proteins in the cell and it is anticipated that an understanding of these modifiers of mGlu receptor function will open new opportunities for pharmacological tool development and new therapeutic strategies. Over the past decade, an increasing number of selective agonists, antagonists, and allosteric modulators have been developed which target distinct mGlu receptor subtypes; many of these agents have now been further validated in numerous electrophysiological and behavioral models. The combination of these pharmacological tools, in conjunction with genetic approaches, has led to major advances in our understanding of the roles of mGlu receptors in the regulation of CNS function and animal behavior. These studies suggest the exciting possibility that drugs active at mGlu receptors will be useful in treatment of a wide variety of neurological and psychiatric disorders such as Parkinson's disease, anxiety disorders, and schizophrenia.

This article describes recent advances in the development of subtype-selective, noncompetitive modulators of metabotropic glutamate receptor subtype 1 (mGluR1). mGluR1 plays an important role in modulating synaptic transmission and neuronal excitability via intracellular signal transduction pathways and has been implicated in a number of CNS disorders. Allosteric modulation of mGluR1 by potentiation and antagonism occurs through binding to the seven transmembrane domain. In addition to blocking agonist-dependent responses, many of the antagonists also show inverseagonist activity by blocking constitutive receptor activity. Highly potent and selective mGluR1 radioligands have been used to evaluate receptor binding in vivo and in vitro. Some of these novel agents have demonstrated high levels of CNS exposure and receptor occupancy in vivo, as well as efficacy in a number of preclinical models of neurological disorders.

This article describes recent medicinal chemistry progress toward selective potentiators of the metabotropic glutamate receptor 2 (mGluR2). Groups at Lilly and Merck have identified new classes of potentiators that exhibit selectivity for mGluR2 over the seven other subtypes of mGluRs. Structure-activity relationships as well as pharmacokinetic properties and in vivo activity are reviewed.

Over the last several years a great deal of interest has been focused on the metabotropic glutamate receptors as potential targets for the treatment of a variety of disorders of the central nervous system. Recently, selective agonist or allosteric potentiators of mGluR4, one of the group III mGluRs, have been proposed as potential novel therapeutics for the palliative treatment of Parkinson's disease and some forms of epilepsy. mGluR4 stands out amongst the group III mGluRs due to its relatively restricted localization and apparent role in several key neuronal circuits. Work from a number of laboratories has led to the development of more selective tools for the study of mGluR4, as well as refined models of the structure and function of this receptor. In addition, a growing body of literature suggests that mGluR4 plays a key neuroprotective role in broad spectrum of neurodegenerative disorders. It is hoped that this increased understanding of the role of mGluR4 combined with more detailed structural information will spur the development of better pharmacological tools, and ultimately to novel clinical therapy.

Extensive research into the functions of glutamate and glutamate receptors in the central nervous system (CNS) has shown an essential role of metabotropic glutamate (mGlu) receptors in normal brain functions, but also in neurological and psychiatric disorders. The precise functions of these receptors remain undefined, and progress toward understanding their functions has been hampered by the lack of selective ligands with appropriate pharmacokinetic properties. The Group I mGlu receptor, mGlu5, is well positioned to regulate and fine-tune neuronal excitability and synaptic transmission through its modulation of various signal transduction pathways and interactions with other transmitter systems. Therefore, the mGlu5 receptor may be an important therapeutic target for the treatment of disorders of the central nervous system. The discovery of MPEP 3, a non-competitive mGlu5 receptor antagonist, provided a potent, selective, systemically active tool compound for proof of concept studies in animal models of various disease states. These studies have led to greater understanding of possible therapeutic applications of mGlu5 receptor antagonists in recent years, suggesting their use in a number of disease states, including chronic pain, various psychiatric and neurological disorders, substance abuse and withdrawal, obesity and gastroesophageal reflux disease (GERD). Together, these findings have intensified efforts to find other non-competitive mGlu5 receptor antagonists and have led to the discovery of several second-generation compounds, a few of which are in preclinical evaluations. There have been several recent reviews on mGlu receptor. This article highlights recent efforts on the design, synthesis and development of novel, non-competitive mGlu5 receptor antagonists and studies to understand their in vitro mechanisms of action and in vivo pharmacological profiles. Emphasis is also given to recent advances in the potential therapeutic applications of noncompetitive mGlu5 receptor antagonists.

Metabotropic glutamate receptors (mGluRs) have been implicated in a variety of neurological and psychiatric disorders. This article describes recent progress in the development of agonists and antagonists for mGluR 6, 7, and 8. All of them are conformationally constrained or substituted amino acids, and they act at N-terminal extracellular glutamate binding site. These ligands serve as valuable tools for studying physiological and pathological roles of mGluRs. However, their therapeutic potential may be restricted by their poor CNS penetration and lack of selectivity for individual receptors.