6-methyl-2-(phenylethynyl)pyridine and 3-fluoro-5-((6-methylpyridin-2-yl)ethynyl)benzonitrile

Pre-clinical studies suggest that negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5), including 2-methyl-6-(phenylethynyl)pyridine (MPEP), 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and fenobam are highly effective in attenuating drug-taking and drug-seeking behaviors. However, both MPEP and MTEP have no translational potential for use in humans because of their off-target effects and short half-lives. Here, we report that 3-fluoro-5-[(6-methylpyridin-2-yl)ethynyl]benzonitrile (MFZ 10-7), a novel mGluR5 NAM, is more potent and selective than MPEP, MTEP and fenobam in both in vitro binding and functional assays. Similar to MTEP, intraperitoneal administration of MFZ 10-7 inhibited intravenous cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior and cocaine-associated cue-induced cocaine-seeking behavior in rats. Although MFZ 10-7 and MTEP lowered the rate of oral sucrose self-administration, they did not alter total sucrose intake. Further, MFZ 10-7 appeared to be more potent than MTEP in inducing downward shifts in the cocaine dose-response curve, but less effective than MTEP in attenuating sucrose-induced reinstatement of sucrose-seeking behavior. MFZ 10-7 and MTEP had no effect on basal locomotor behavior. These findings not only provide additional evidence supporting an important role for mGluR5 in cocaine reward and addiction, but also introduce a new tool for both in vitro and in vivo investigations with which to further characterize this role.

Topics: Allosteric Regulation; Analysis of Variance; Animals; Binding, Competitive; Cocaine; Cues; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Antagonists; HEK293 Cells; Humans; Imidazoles; In Vitro Techniques; Infusions, Intravenous; Inhibitory Concentration 50; Male; Motor Activity; Nitriles; Piperidines; Pyridines; Random Allocation; Rats; Receptor, Metabotropic Glutamate 5; Reinforcement Schedule; Reward; Secondary Prevention; Self Administration; Sucrose; Thiazoles