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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENTCOOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 10 September 2010 (10.09.2010) WO 2010/101648 Al (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, AOlN 37/18 (2006.01) AOlK 31/16 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (21) International Application Number: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, PCT/US20 10/000669 ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (22) International Filing Date: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 4 March 2010 (04.03.2010) SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 12/381,086 6 March 2009 (06.03.2009) US ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, (72) Inventor; and ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant : WOOD, Richard D. [US/US]; 16 Decision MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, Way West, Washington Crossing, PA 18977 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors: WELSH, William, J.; 66 Maybury Hill Road, Princeton, NJ 08540 (US). AI, Ni; 11 Halley Court, Pis- Declarations under Rule 4.17: cataway, NJ 08854 (US). EKINS, Sean; 601 Run- — of inventorship (Rule 4Λ 7(iv)) neymede Avenue, Jenkintown, PA 19046 (US). Published: (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, — with international search report (Art. 21(3)) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (54) Title: GLUTAMATE RECEPTOR MODULATORS AND THERAPEUTIC AGENTS (57) Abstract: The present invention discloses methods of modulating the activity of Group I mGluRs using a defined class of benzamide compounds. In one embodiment, methods of modulating the activity of mGluRl are provided. In another embodiment, methods of modulating the activity of mGluR5 are provided. In still another embodiment, methods of simultaneously modulating the activities of both mGluRl and mGluR5 are provided. The present invention also provides methods of treating diseases or dis- orders which are mediated in full or in part by Group I mGluRs using one or more compounds belonging to the defined class of benzamide compounds. The present invention further provides methods of preventing diseases or disorders which are mediated in full or in part by Group I mGluRs using one or more compounds belonging to the defined class of compounds. Diseases and dis- orders contemplated include, inter alia, diseases and disorders of the central nervous system, the peripheral nervous system, the gastrointestinal system, the circulatory system, skin, retina, brain, heart, and lungs. GLUTAMATE RECEPTOR MODULATORS AND THERAPEUTIC AGENTS INVENTORS: Richard D. Wood, Washington Crossing, PA William J. Welsh, Princeton, NJ Sean Ekins, Jenkintown, PA Ni Ai, Piscataway, NJ CROSS-REFERENCES TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 12/381,086, filed March 6, 2009. FIELD OF THE INVENTION The invention relates to compounds and methods to use compounds to treat diseases or disorders mediated in full or in part by Group 1 metabotropic glutamate receptors. BACKGROUND OF THE INVENTION Several diseases and disorders are mediated by improper functioning of glutamate receptors. Because excitatory amino acid receptors in general and mGluRs in particular are implicated in diverse normal physiological processes, there is a need to identify compounds capable of modulating receptor-mediated functions. For example, partial antagonism of mGluRs might be clinically useful in treating disorders wherein the process mediated by the receptor is pathologically enhanced. Partial antagonism might be clinically useful in treating disorders wherein the is an overabundance of the indigenous ligand stimulating the receptor to induce a critical function. There is a need to identify and develop methods of treatment and methods of prevention of disorders related to the improper functioning of mGluRs and specifically those in Group I. BRIEF DESCRIPTION OF THE INVENTION The present invention discloses methods of modulating the activity of Group I mGluRs using a defined class of compounds. Surprisingly, it was found that selected benzamide compounds modulated the activity of Group 1 mGluRs. In one embodiment, methods of modulating the activity of mGluRI are provided. In another embodiment, methods of modulating the activity of mGluR5 are provided. In still another embodiment, methods of simultaneously modulating the activities of both mGluRI and mGluR5 are provided. The present invention also provides methods of treating diseases or disorders which are mediated in full or in part by Group I mGluRs using one or more compounds belonging to the defined class of benzamide compounds. The present invention further provides methods of preventing diseases or disorders which are mediated in full or in part by Group I mGluRs using one or more compounds belonging to the defined class of benzamide compounds. Diseases and disorders contemplated include, but are not limited to, diseases and disorders of the central nervous system, the peripheral nervous system, the gastrointestinal system, the circulatory system, skin, retina, brain, heart, and lungs. It will be clear to those with skill in the art that the distribution and function of Group 1 mGluRs in animals is not completely understood, and that diseases or disorders in which Group 1 mGluRs are implicated, whether known at the present or unveiled in the future, are contemplated and are within the scope of the instant invention. BRIEF DESCRIPTION OF THE DRAWINGS Figure I graphically portrays the ability of Compound 1 and Compound 2 1 to reverse hyperalgesia in the partial sciatic nerve ligation (PSN) model of neuropathic pain in the rat, as compared to gabapentin, when dosed intrathecally. Figure Il graphically portrays the ability of Compound 1 to reverse hyperalgesia in the partial sciatic nerve ligation (PSN) model of neuropathic pain in the rat, as compared to gabapentin, when dosed orally. Figure III graphically portrays the ability of Compound 5 to reverse hyperalgesia in the partial sciatic nerve ligation (PSN) model of neuropathic pain in the rat, as compared to gabapentin, when dosed orally. DETAILED DESCRIPTION OF THE INVENTION According to the present invention, selective allosteric modulators with specificity for either mGluRI or mGluR5 are provided. The mGlui and mGlu receptors exhibit different patterns of expression in the CNS, suggesting distinct functions for each receptor. mGluR5 receptors are expressed with high to moderate density in frontal cortex, caudate, putamen, nucleus accumbens, olfactory tubercle, hippocampus, and dorsal horn of the spinal cord, whereas low levels of expression are observed in the cerebellum. In contrast, mGluRI receptor is expressed in high density in the cerebellum, but low to moderate expression is observed in frontal cortex, caudate, putamen, nucleus accumbens, and olfactory tubercle. Therefore it is understood that allosteric modulators selective for mGluRI might produce physiological effects distinct from those produced by allosteric modulators selective for mGluR5. Negative allosteric modulators with affinity for either mGluRI or mGluR5 will produce effects at the receptor which may include the induction of a change in receptor conformation resulting in a diminished affinity of the endogenous ligand for the primary binding site, and decrease of physiologic function of the activated receptor. Such functional modulation may lead to decreased phosphoinositide hydrolysis, decreased mobilization of intracellular Ca2+, and decreased activation of protein kinase C. Conversely, positive allosteric modulators with affinity for either mGluRI or mGluR δ might produce effects at the receptor which may include an enhancement of affinity of the endogenous ligand for the primary binding site or a subsequent enhancement of the normal physiologic function of the activated receptor. The present invention is directed to methods of treating a disease or disorder which is mediated fully or in part by mGluRI or mGluR δ using compounds of Formula I, and pharmaceutically acceptable salts, prodrugs, enantiomers, or hydrates thereof: Formula I wherein R1 = H , SH, NHR6, or OR6; R2 and R3 are independently selected from fused phenyl, H, lower alkyl, I Br, Cl, F, CF3, CH2CF3, CH2Ph, CH=CH 2, CsCH, OCH 3, OCF3, Ph OPh, and NO2; R4 is selected from the group consisting of H, lower alkyl, I, Br, Cl, F, CF3, CH2CF3, CH2Ph, CH=CH 2, CsCH, C N , OCH 3, OCF 3, Ph1 OPh, and NO2; R5 is H lower alkyl, or phenyl; R6 is selected from the group consisting of H , COCH 3, COCH 2CH3, COCH(CH 3)2 COC(CH 3)3, COPh, COCH 2Ph, COC6H4NO2(p), COC6H4OH(P), COC 6H4NH2(P), CON(CH ) , CON(CH CHa) , CON(CH )(CH CH ), CON(CH Ph) CON(CH )(CH Ph), 1- 3 2 2 2 3 2 3 2 2 1 3 2 pyrrolidinecarbonyl, 2-carboxy-1-pyrrolidincarbonyl, (2S)- 2-carboxy-1- pyrrolidinecarbonyl, (2R)- 2-carboxy-1-pyrrolidinecarbonyl, 1-morpholinecarbonyl,
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    REVIEW ARTICLE published: 22 July 2014 doi: 10.3389/fgene.2014.00239 Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders Steven M. Colvin and Kenneth Y. Kwan* Department of Human Genetics – The Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, USA Edited by: A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is Peter Kennedy Todd, University of essential for the development of targeted molecular therapies. For fragile X syndrome Michigan, USA (FXS), recent mechanistic studies have been focused on the metabotropic glutamate Reviewed by: receptor (mGluR) signaling pathway. This line of research has led to the discovery Maria Paola Lombardi, University of Amsterdam, Netherlands of promising candidate drugs currently undergoing various phases of clinical trial, and Rhiannon Meredith, VU University represents a model of how biological insights can inform therapeutic strategies in Amsterdam, Netherlands neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which Christina Gross, Cincinnati Children’s Hospital Medical Center, USA targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the *Correspondence: Kenneth Y. Kwan, Department of disorder is expected to inform additional therapeutic strategies. Alterations in the assembly Human Genetics – The Molecular and of neural circuits in the neocortex have been recently implicated in genetic studies of autism Behavioral Neuroscience Institute, and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated University of Michigan Medical School, 5041 BSRB, 109 Zina Pitcher nitric oxide signaling in the developing neocortex as a novel candidate mechanism of Place, Ann Arbor, MI 48109-2200, FXS.
  • Optical Control of Pain in Vivo with a Photoactive Mglu5 Receptor

    Optical Control of Pain in Vivo with a Photoactive Mglu5 Receptor

    RESEARCH ARTICLE Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator Joan Font1,2,3†, Marc Lo´ pez-Cano4,5†, Serena Notartomaso6, Pamela Scarselli6, Paola Di Pietro6, Roger Bresolı´-Obach7, Giuseppe Battaglia6, Fanny Malhaire8, Xavier Rovira8, Juanlo Catena1, Jesu´s Giraldo2,3,9, Jean-Philippe Pin8, Vı´ctorFerna´ ndez-Duen˜ as4,5, Cyril Goudet8, Santi Nonell7, Ferdinando Nicoletti6,10, Amadeu Llebaria1*, Francisco Ciruela4,5* 1MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain; 2Institut de Neurocie`ncies, Universitat Auto`noma de Barcelona, Bellaterra, Spain; 3Unitat de Bioestadı´stica, Universitat Auto`noma de Barcelona, Bellaterra, Spain; 4Departament de Patologia i Terape`utica Experimental, Facultat de Medicina i Cie`ncies de la Salut, IDIBELL, Universitat de Barcelona, Barcelona, Spain; 5Institut de Neurocie`ncies, Universitat de Barcelona, Barcelona, Spain; 6I.R.C.C.S. Neuromed, Pozzilli, Italy; 7Institut Quı´mic de Sarria`, Universitat Ramon Llull, Barcelona, Spain; 8IGF, CNRS, INSERM, Univ. Montpellier, Montpellier, France; 9Network Biomedical Research Center on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; 10Department of Physiology and Pharmacology, University Sapienza, Rome, Italy *For correspondence: amadeu. Abstract Light-operated drugs constitute a major target in drug discovery, since they may [email protected] (AL); provide spatiotemporal resolution for the treatment of complex diseases (i.e. chronic pain). JF-NP- [email protected] (FC) 26 is an inactive photocaged derivative of the metabotropic glutamate type 5 (mGlu5) receptor †These authors contributed negative allosteric modulator raseglurant. Violet light illumination of JF-NP-26 induces a equally to this work photochemical reaction prompting the active-drug’s release, which effectively controls mGlu5 receptor activity both in ectopic expressing systems and in striatal primary neurons.