Bivalent Ligands That Target 渭 Opioid (MOP) and Cannabinoid1 (CB1) Receptors Are Potent Analgesics Devoid of Tolerance

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• 作者：Morgan Le Naour ; Eyup Akg眉n ; Ajay Yekkirala ; Mary M. Lunzer ; Mike D. Powers ; Alexander E. Kalyuzhny ; Philip S. Portoghese
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5505-5513
• 全文大小：348K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

Given that 渭 opioid (MOP) and canabinoid (CB₁) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB₁) in cultured cells, the possibility of functional, endogenous MOP-CB₁ in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1鈥?b>5 that contain both 渭 agonist and CB₁ antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB₁ receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2鈥?b>5 produced tolerance in mice, MOR-CB₁ apparently is not an important target for reducing tolerance.