Novel Non-Peptide Nociceptin/Orphanin FQ Receptor Agonist, 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: Design, Synthesis, and Structure−Activi

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• 作者：Shigeo Hayashi ; Akiko Hirao ; Aki Imai ; Hiroshi Nakamura ; Yoshinori Murata ; Katsuyo Ohashi ; Eriko Nakata
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：February 12, 2009
• 年：2009
• 卷：52
• 期：3
• 页码：610-625
• 全文大小：302K
• 年卷期：v.52,no.3(February 12, 2009)
• ISSN：1520-4804

文摘

An endogenous heptadecapeptide, nociceptin/orphanin FQ (N/OFQ), and a G-protein-coupled receptor, N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor], have been described in terms of its structure, distribution, and pharmacology. Thus, the N/OFQ and NOP receptor are located in the central nervous systems in humans, primates, and rodents, and are involved in the integration of the emotional components in the brain; e.g., N/OFQ displays anxiolytic activity in the brain. For identifying orally potent anxiolytic, drug-design studies were performed with a series of 1,2-disubstituted benzimidazole derivatives, which resulted in the identification of various chemotypes of highly potent NOP selective full agonists in vitro with high or moderate NOP receptor occupancy in the mice brain per os such as 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole 1 (MCOPPB), the most potent novel non-peptide NOP full agonist in vitro and an orally potent anxiolytic in the mice.