In vivo characterization of (-)(-)MCL-144 and (+)(-)MCL-193: Isomeric, bivalent ligands with Mu/Kappa agonist properties
In vivo characterization of (-)(-)MCL-144 and (+)(-)MCL-193: Isomeric, bivalent ligands with Mu/Kappa agonist properties
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DOI：
10.1007/s11064-008-9752-3
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发表时间：
2008-10-01
影响因子：
4.4
通讯作者：
Bidlack, Jean M.
中科院分区：
文献类型：
--
作者：
Mathews, Jennifer L.;Fulton, Brian S.;Bidlack, Jean M.
一旦阿片受体二聚体被假设，目标就是合成和筛选新型阿片类药物，希望加深我们对阿片配体与阿片受体的结构-活性关系的了解。本研究的目的是解决两种异构二价配体在体内集中给药后是否会有药理学差异。这两种化合物，（-）二（N-环丁基甲基-吗啡喃-3-基）癸二酸酯二盐酸盐（MCL-144）和1-（（+）N-环丁基甲基吗啡喃-3-基）-10-（（-）N-环丁基甲基吗啡喃-3-基）癸二酸酯（MCL-193）各自通过10-碳链酯连接。两种配体的活性（-）对映异构体是3-羟基-N-环丁基甲基吗啡喃（（-）MCL-101），环啡烷的N-环丁基甲基类似物（J Med Chem 43：114-122，2000）。MCL-144含有两个活性左旋（-）（-）药效团，而MCL-193含有MCL-101的一个活性（-）和一个非活性（+）药效团。体外分析表明，所有三种化合物（-）（-）MCL-144、（+）（-）MCL-193和（-）MCL-101都是κ激动剂和μ部分激动剂。与（+）（-）MCL-193相比，（-）（-）MCL-144和（-）MCL-101对μ和κ阿片样物质受体具有高得多的亲和力。在体内，（-）（-）MCL-144和（+）（-）MCL-193在55 C甩尾试验中产生完整的剂量-反应曲线，在脑室内（i. c. v.）局这两种化合物的镇痛特性被μ-选择性拮抗剂β-funaltamine和κ-选择性拮抗剂nor-binaltorphimine拮抗。伴随，i. c. v.，（-）（-）MCL-144或（+）（-）MCL-193与吗啡一起给药，在任何测试剂量下都没有显著拮抗吗啡诱导的抗伤害感受。在抗伤害感受性试验中，（-）（-）MCL-144和（+）（-）MCL-193具有相同的药理学性质，表明具有由10个碳间隔基团隔开的两个活性药效团不会增加化合物的抗伤害感受性功效。此外，比较（-）（-）MCL-145和（-）（-）MCL-144也是有意义的，因为这些二价配体之间的唯一差异是连接两个药效团的间隔区，但（-）（-）MCL-145产生的艾德（50）值比（-）（-）MCL-144低10倍（艾德（50）值= 0.3 nmol和3.0 nmol，分别）。
Once opioid receptor dimers were postulated, a goal has been to synthesize and screen novel opioids, with the hope of furthering our knowledge of the structure-activity relationship of opioid ligands with the opioid receptors. The aim of the current study was to address whether two isomeric bivalent ligands would have pharmacological differences after central administration, in vivo. The two compounds, (-) bis(N-cyclobutylmethyl-morphinan-3-yl) sebacoylate dihydrochloride (MCL-144) and 1-((+)N-cyclobutylmethylmorphinan-3-yl)-10-((-) N-cyclobutylmethylmorphinan-3-yl)sebacolyate (MCL-193) are each linked by a 10-carbon chain ester. The active (-) enantiomer for both ligands is 3-hydroxy-N-cyclobutylmethyl morphinan ((-)MCL-101), a N-cyclobutylmethyl analogue of cyclorphan (J Med Chem 43:114-122, 2000). MCL-144 contains two active levo rotatory (-)(-) pharmacophores, while MCL-193 contains one active (-) and one inactive (+) pharmacophore of MCL-101. In vitro analysis demonstrated that all three compounds, (-)(-)MCL-144, (+)(-)MCL-193 and (-)MCL-101 were kappa agonists and mu partial agonists. (-)(-)MCL-144 and (-)MCL-101 had much higher affinity for both the mu and kappa opioid receptors compared to (+)(-)MCL-193. In vivo, (-)(-)MCL-144 and (+)(-)MCL-193 produced full dose-response curves, in the 55C tail-flick test, with each compound having an ED(50) value of 3.0 nmol after intracerebroventricular (i.c.v.) administration. The analgesic properties of both compounds were antagonized by the mu-selective antagonist, beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. Concomitant, i.c.v., administration of either (-)(-)MCL-144 or (+)(-)MCL-193 with morphine, did not significantly antagonize morphine-induced antinociception at any dose tested. In antinociceptive tests, (-)(-)MCL-144 and (+)(-)MCL-193 had the same pharmacological properties, demonstrating that having two active pharmacophores separated by a 10-carbon spacer group did not increase the antinociceptive efficacy of the compound. Additionally, it was also of interest to compare (-)(-)MCL-145 and (-)(-)MCL-144, as the only difference between these bivalent ligands is the spacer region connecting the two pharmacophores, yet (-)(-)MCL-145 produced an ED(50) value 10-fold lower than (-)(-)MCL-144 (ED(50) values = 0.3 nmol and 3.0 nmol, respectively).