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

• Published in: Journal of medicinal chemistry Vol. 49; no. 3; pp. 1080 - 1100
• Main Authors: Iso, Yasuyoshi, Grajkowska, Ewa, Wroblewski, Jarda T, Davis, Jared, Goeders, Nicholas E, Johnson, Kenneth M, Sanker, Subramaniam, Roth, Bryan L, Tueckmantel, Werner, Kozikowski, Alan P
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.02.2006; Amer Chemical Soc
• Subjects: Allosteric Site; Animals; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Cocaine - administration & dosage; Cocaine-Related Disorders - prevention & control; Cricetinae; Cricetulus; Glutamatergic system (aspartate and other excitatory aminoacids); Humans; Life Sciences & Biomedicine; Ligands; Male; Medical sciences; Narcotics - administration & dosage; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Radioligand Assay; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Science & Technology; Self Administration; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; ACID; 2-METHYL-6-(PHENYLETHYNYL)-PYRIDINE; IN-VIVO; BIOLOGICAL EVALUATION; RATS; ANXIOLYTIC ACTIVITY; MGLU5 RECEPTOR; MPEP; HIGHLY POTENT; NUCLEUS-ACCUMBENS; Group I mglu glutamate receptor; Nitrile; mglu5 glutamate receptor; Acetylenic compound; CNS stimulant; Psychotropic; Thiazole derivatives; Glutamate receptor; In vitro; Pyridine derivatives; Structure activity relation; Metabotropic receptor; Cocaine; Drug of abuse; Antagonist; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050570f

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.