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Synthesis and Structure−Activity Relationships of 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine Analogues as Potent, Noncompetitive Metabotropic Glutamate Receptor Subtype 5 Antagonists; Search for Cocaine Medications

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Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, Department of Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, D.C. 20007, Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, Louisiana 71130-3932, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and Acenta Discovery Inc., South Rita Road, Suite 300, Tucson, Arizona 85747
Cite this: J. Med. Chem. 2006, 49, 3, 1080–1100
Publication Date (Web):January 7, 2006
https://doi.org/10.1021/jm050570f
Copyright © 2006 American Chemical Society
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Abstract

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Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5 field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the reinstatement of cocaine self-administration caused by the presentation of environmental cues previously associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of gaining a better understanding of the structural features relevant to its antagonist potency and with the ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine. These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists that are 490 and 230 times, respectively, better than that of MTEP.

 University of Illinois at Chicago.

 Georgetown University Medical Center.

§

 LSU Health Sciences Center.

 University of Texas Medical Branch.

 Case Western Reserve University School of Medicine.

#

 Acenta Discovery Inc.

*

 To whom correspondence should be addressed. Phone:  312-996-7577. Fax:  312-996-7107. E-mail:  [email protected]

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HPLC, HRMS, and elemental analysis data for compounds in Tables 2−5. This material is available free of charge via the Internet at http://pubs.acs.org.

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