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NEUROPHARMACOLOGY

ADX47273 [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: A Novel Metabotropic Glutamate Receptor 5-Selective Positive Allosteric Modulator with Preclinical Antipsychotic-Like and Procognitive Activities

Wyeth Neuroscience Discovery Research, Princeton, New Jersey (F.L., S.G., C. K., R.N., R.G., G.Z., P.J.A., M.P., C.W., X.K., D.S., M.O., E.K., M.L., F.P., C.P., M.H.P., N.J.B., C.E.B., T.A.C., S.L., S.R.-L., K.L.M.); Wyeth Translational Medicine, Collegeville, Pennsylvania (M.D.); and Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, Pearl River, New Jersey (A.G.)

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-D-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca²⁺ assays (EC₅₀ = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 µM) and competed for binding of [³H]2-methyl-6-(phenylethynyl)pyridine (K_i = 4.3 µM), but not [³H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.

Address correspondence to: Dr. Feng Liu, Discovery Neuroscience, Wyeth Discovery, 865 Ridge Road, Monmouth Junction, NJ 08852. E-mail: liuf2{at}wyeth.com