双价配体靶向 μ 阿片（MOP）和大麻素 1（CB1）受体，是一种强效的无耐受镇痛剂。
Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance.
机构信息
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , Minneapolis, Minneapolis 55455, United States.
出版信息
J Med Chem. 2013 Jul 11;56(13):5505-13. doi: 10.1021/jm4005219. Epub 2013 Jun 20.
Abstract
Given that μ 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 1-5 that contain both μ 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 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance.
摘要
鉴于 μ 阿片受体（MOP）和大麻素受体（CB1）在中枢神经系统的不同区域共存，并在培养细胞中被报道为异源二聚体（MOP-CB1），因此在伤害感受和其他药理作用中存在功能性、内源性 MOP-CB1 的可能性被提出。作为研究这种可能性的第一步，我们合成了一系列包含 μ 激动剂和 CB1 拮抗剂药效团的双价配体 1-5，用作研究体内 MOP 和 CB1 受体功能相互作用的工具。在共表达两种受体的 HEK293 细胞上进行的免疫荧光研究表明，5（20 个原子间隔物）是该系列中唯一能够桥接异源二聚体的前体的成员。在小鼠中的镇痛测试表明，5 是该系列中最有效的成员。由于混合物的单价配体 9 + 10 或双价配体 2-5 在小鼠中均未产生耐受性，因此 MOR-CB1 显然不是减少耐受性的重要靶标。
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