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      Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype-2 and -3 (mGlu 2/3) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment in a Rat Model of Cocaine Dependence

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          Abstract

          As part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor positive allosteric modulator (PAM) research, we performed structure–activity relationship (SAR) studies around a series of group II mGlu PAMs. Initial analogues exhibited weak activity as mGlu 2 receptor PAMs and no activity at mGlu 3. Compound optimization led to the identification of potent mGlu 2/3 selective PAMs with no in vitro activity at mGlu 1,4–8 or 45 other CNS receptors. In vitro pharmacological characterization of representative compound 44 indicated agonist-PAM activity toward mGlu 2 and PAM activity at mGlu 3. The most potent mGlu 2/3 PAMs were characterized in assays predictive of ADME/T and pharmacokinetic (PK) properties, allowing the discovery of systemically active mGlu 2/3 PAMs. On the basis of its overall profile, compound 74 was selected for behavioral studies and was shown to dose-dependently decrease cocaine self-administration in rats after intraperitoneal administration. These mGlu 2/3 receptor PAMs have significant potential as small molecule tools for investigating group II mGlu pharmacology.

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          Pharmacology and functions of metabotropic glutamate receptors.

          P Conn, J P Pin (1997)
          In the mid to late 1980s, studies were published that provided the first evidence for the existence of glutamate receptors that are not ligand-gated cation channels but are coupled to effector systems through GTP-binding proteins. Since those initial reports, tremendous progress has been made in characterizing these metabotropic glutamate receptors (mGluRs), including cloning and characterization of cDNA that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing new highly selective mGluR agonists and antagonists and toward determining the physiologic roles of the mGluRs in mammalian brain. These findings have exciting implications for drug development and suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.
          Article 0 comments Cited 311 times – based on 0 reviews     Review now
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            Regulation of neurotransmitter release by metabotropic glutamate receptors.

            Jayne Cartmell, Darryle D Schoepp (2000)
            The G protein-coupled metabotropic glutamate (mGlu) receptors are differentially localized at various synapses throughout the brain. Depending on the receptor subtype, they appear to be localized at presynaptic and/or postsynaptic sites, including glial as well as neuronal elements. The heterogeneous distribution of these receptors on glutamate and nonglutamate neurons/cells thus allows modulation of synaptic transmission by a number of different mechanisms. Electrophysiological studies have demonstrated that the activation of mGlu receptors can modulate the activity of Ca(2+) or K(+) channels, or interfere with release processes downstream of Ca(2+) entry, and consequently regulate neuronal synaptic activity. Such changes evoked by mGlu receptors can ultimately regulate transmitter release at both glutamatergic and nonglutamatergic synapses. Increasing neurochemical evidence has emerged, obtained from in vitro and in vivo studies, showing modulation of the release of a variety of transmitters by mGlu receptors. This review addresses the neurochemical evidence for mGlu receptor-mediated regulation of neurotransmitters, such as excitatory and inhibitory amino acids, monoamines, and neuropeptides.
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              Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia.

              P. Conn, Craig W. Lindsley, Carrie K. Jones (2009)
              In recent years, the metabotropic glutamate (mGlu) receptors have emerged as potential new drug targets for treatment of a range of CNS disorders. Some of the most compelling advances have been made in targeting specific mGlu receptor subtypes as a fundamentally new approach to the treatment of schizophrenia. Recent animal and clinical studies provide strong evidence that agonists of group II mGlu receptors (mGluR2 and mGluR3) are effective in the treatment of the positive symptoms of schizophrenia, and animal studies suggest that mGluR5 agonists could provide a novel approach for the treatment of all major symptom domains (positive, negative, and cognitive) of this disorder. Although the discovery of selective agonists of these receptors is a challenge, there have been recent advances in the discovery of highly selective positive allosteric modulators (PAMs) of mGluR2 and mGluR5. These mGlu receptor-selective PAMs have properties needed for optimization as clinical candidates and have robust effects in animal models that predict efficacy in treatment of schizophrenia.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Med Chem
                Journal ID (iso-abbrev): J. Med. Chem
                Journal ID (publisher-id): jm
                Journal ID (coden): jmcmar
                Title: Journal of Medicinal Chemistry
                Publisher: American Chemical Society
                ISSN (Print): 0022-2623
                ISSN (Electronic): 1520-4804
                Publication date PMC-release: 15 April 2015
                Publication date (Electronic): 15 April 2014
                Publication date (Print): 22 May 2014
                Volume: 57
                Issue: 10
                Pages: 4154-4172
                Affiliations
                [† ]Cell Death and Survival Networks Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , 10901 N. Torrey Pines Road, La Jolla, California 92037, United States
                [2] ‡Department of Pharmacology, §Department of Pathology, and ∥Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States
                [⊥ ]Department of Psychiatry, School of Medicine, University of California—San Diego , La Jolla, California 92093, United States
                Author notes
                [* ]Phone: 858-646-3100. Fax: 858-795-5225. E-mail: ncosford@ 123456sanfordburnham.org .
                Article
                DOI: 10.1021/jm5000563
                PMC ID: 4033659
                PubMed ID: 24735492
                SO-VID: 360d37af-e724-4206-b06d-98c2f999415e
                Copyright © Copyright © 2014 American Chemical Society
                History
                Date received : 10 January 2014
                Funding
                National Institutes of Health, United States
                Categories
                Subject: Article
                Custom metadata
                document-id-old-9 jm5000563
                document-id-new-14 jm-2014-000563
                ccc-price

                ScienceOpen disciplines: Pharmaceutical chemistry
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                ScienceOpen disciplines: Pharmaceutical chemistry

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