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NEUROPHARMACOLOGY

Radioligand Binding Properties and Pharmacological Characterization of 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a High-Affinity, Selective, and Noncompetitive Antagonist of Metabotropic Glutamate Receptor Type 1

Neuroscience Research, Pharmacology Laboratories (A.K., T.T., S.T., T.W., Y.N., Y.S., M.O.), Molecular Medicine Laboratory, Molecular Laboratories (S.K.), and Chemistry Laboratory I, Chemistry Laboratories (S.H.), Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan

Metabotropic glutamate receptor type 1 (mGluR1) is thought to play important roles in the neurotransmission and pathogenesis of several neurological disorders. Here, we describe the radioligand binding properties and pharmacological effects of a newly synthesized, high-affinity, selective, and noncompetitive mGluR1 antagonist, 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198). YM-298198 inhibited glutamate-induced inositol phosphate production in mGluR1-NIH3T3 cells with an IC₅₀ of 16 ± 5.8 nM in a noncompetitive manner. Its radiolabeled form, [³H]YM-298198, bound to mGluR1-NIH3T3 cell membranes with a K_D of 32 ± 8.5 nM and a B_max of 2297 ± 291 fmol/mg protein. In ligand displacement experiments using rat cerebellum membrane, an existing noncompetitive mGluR1 antagonist 7-(hydroxyimino)cyclo-propa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) competitively displaced [³H]YM-298198 binding, although glutamate and other mGluR1 ligands acting on a glutamate site failed to inhibit [³H]YM-298198 binding, suggesting that YM-298198 binds to CPCCOEt (allosteric) binding sites but not to glutamate (agonist) binding sites. Specificity was demonstrated for mGluR1 over mGluR subtypes 2 to 7, ionotropic glutamate receptors, and other receptor, transporter, and ion channel targets. In in vivo experiments, orally administered YM-298198 showed a significant analgesic effect in streptozotocin-induced hyperalgesic mice at doses (30 mg/kg) that did not cause Rotarod performance impairment, indicating that it is also useful even for in vivo experiments. In conclusion, YM-298198 is a newly synthesized, high-affinity, selective, and noncompetitive antagonist of mGluR1 that will be a useful pharmacological tool due to its highly active properties in vitro and in vivo. Its radiolabeled form [³H]YM-298198 will also be a valuable tool for future investigation of the mGluR1.

Address correspondence to: Dr. Masamichi Okada, Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, 305-8585, Japan. E-mail: masamichi.okada{at}jp.astellas.com

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