2-Methyl-6-(phenylethynyl)pyridine (3), a potent noncompetitive mGlu5 receptor antagonist widely used to characterize the pharmacology of mGlu5 receptors, suffers from a number of shortcomings as a therapeutic agent, including off-target activity and poor aqueous solubility. Seeking to improve the properties of 3 led to the synthesis of compound 9, a highly selective mGlu5 receptor antagonist that is 5-fold more potent than 3 in the rat fear-potentiated startle model of anxiety.

Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller-Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders.

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The binding of [3 H]methoxymethyl-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (methoxymethyl-MTEP), a potent and selective antagonist for metabotropic glutamate (mGlu)5 receptors, was characterized in rat brain both in vitro and in vivo. Nonspecific binding, as defined with 10 M 2-methyl-6-(phenylethynyl)-pyridine (MPEP), was less than 10% of total binding in rat brain membranes. , 1997). There are eight mGluR subtypes, which are subdivided into three groups principally based on sequence homology, but also on signal transduction pathways and agonist selectivity (Nakanishi, 1992;Pin and Duvoisin, 1995). Group I mGluRs initiate cell responses through G q/11 protein coupling to phospholipase C and stimulation of phosphoinositide hydrolysis. In contrast, group II and group III mGluRs are negatively coupled via G i /G o to adenylyl cyclase and reduce forskolinstimulated increases in cAMP in recombinant expression systems. Group I receptors are selectively activated by dihydroxyphenylglycine (DHPG), group II receptors can be stimulated by (2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine and (ϩ)-2-aminobicyclo[3.1.0]-hexane-2,6-dicarboxylate monohydrate (LY354740), and group III receptors are selectively stimulated by L-(ϩ)-2-amino-4-phosphonobutyric acid and (R,S)-4-phosphonophenylglycine (Schoepp et al., 1999).Group I mGluRs include the mGlu1 and mGlu5 subtypes. These two receptors exhibit a regional pattern of expression in the central nervous system, suggesting distinct, functional roles for each receptor (Spooren et al., 2001). For example, expression of mGlu5 receptor protein is high-to-moderate in frontal cortex, caudate putamen, nucleus accumbens, olfacArticle, publication date, and citation information can be found at

The metabotropic glutamate receptor subtype mGlu5 modulates central reward pathways. Many transmitter systems within reward pathways affect feeding. We examined the potential role of mGlu5 in body weight regulation using genetic and pharmacological approaches. Adult mice lacking mGlu5, mGluR5 Ϫ/Ϫ , weighed significantly less than littermate controls (mGluR5 ϩ/ϩ ), despite no difference in ad libitum food intake. After overnight food deprivation, mGluR5Ϫ/Ϫ mice ate significantly less than their mGluR5 ϩ/ϩ controls when refeeding. When on a high fat diet, mGluR5Ϫ/Ϫ mice weighed less and had decreased plasma insulin and leptin concentrations. The selective mGlu5 antagonist MTEP [3-[(2-methyl-1,3-thiazol-4-yl)-ethynyl]-pyridine; 15 mg/kg s.c.] reduced refeeding after overnight food deprivation in mGluR5 ϩ/ϩ , but not mGluR5 Ϫ/Ϫ mice, demonstrating that feeding suppression is mediated via a mGlu5 mechanism. MTEP (1-10 mg/kg) decreased night-time food intake in rats in a dose-related manner. At 10 mg/kg, MTEP injected at 8.5, 4.5, or 0.5 h before refeeding reduced overnight food intake by approximately ϳ30%. Diet-induced obese (DIO) and age-matched lean rats were treated for 12 days with MTEP (3 or 10 mg/kg/day s.c.), dexfenfluramine (3 mg/kg/day s.c.), or vehicle. Daily and cumulative food intakes were reduced in DIO rats by MTEP and dexfenfluramine. Weight gain was prevented with MTEP (3 mg/kg), and weight and adiposity loss was seen with MTEP (10 mg/kg) and dexfenfluramine. Caloric efficiency was decreased, suggesting increased energy expenditure. In lean rats, similar, although smaller, effects were observed. In conclusion, using genetic and pharmacological approaches, we have shown that mGlu5 modulates food intake and energy balance in rodents.