A MOR Antagonist with High Potency and Antagonist Efficacy among Diastereomeric C9-Alkyl-Substituted N-Phenethyl-5-(3-hydroxy)phenylmorphans.
A MOR Antagonist with High Potency and Antagonist Efficacy among Diastereomeric C9-Alkyl-Substituted N-Phenethyl-5-(3-hydroxy)phenylmorphans.
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DOI：
10.3390/molecules28145411
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发表时间：
2023-07-14
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--
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5-（3-羟基）苯基吗啡烷结构类化合物与经典吗啡烷、4，5-环氧吗啡烷和6，7-苯并吗啡烷不同，因为它们具有赤道取向的芳环，而不是经典阿片类中发现的该环的轴向取向。这种修饰和简化的阿片样结构已被证明保留了抗伤害活性，这取决于其立体化学和取代基，其中一些已被发现比吗啡更有效。一个简单的C9-羟基-5-（3-羟基）苯基吗啉对映体被发现是约500倍，更有效的吗啡在体内。我们以前已经研究了N-苯乙基-5-（3-羟基）苯基吗啉类化合物中的C9-烯基和羟烷基取代基。尚未探索可比较的C9-烷基（甲基至丁基）取代基及其非对映异构体组。现在已经合成了所有这些化合物，以确定分子中C9位置的链长和立体化学对其与阿片受体相互作用的影响。我们现在报告的合成和体外活性的16个化合物，C9-甲基，乙基，丙基和丁基非对映异构体，使用抑制毛喉素诱导的cAMP积累试验。发现几种有效的（亚纳摩尔和纳摩尔）莫尔化合物是具有不同功效的选择性激动剂。最令人感兴趣的是，发现了一种选择性莫尔拮抗剂;它在体外不显示任何DOR或KOR激动剂活性，比纳洛酮有效三倍，并且发现在莫尔下拮抗芬太尼的EC 90的程度大于纳洛酮。
The 5-(3-hydroxy)phenylmorphan structural class of compounds are unlike the classical morphinans, 4,5-epoxymorphinans, and 6,7-benzomorphans, in that they have an equatorially oriented aromatic ring rather than the axial orientation of that ring found in the classical opioids. This modified and simplified opioid-like structure has been shown to retain antinociceptive activity, depending on its stereochemistry and substituents, and some of them have been found to be much more potent than morphine. A simple C9-hydroxy-5-(3-hydroxy)phenylmorphan enantiomer was found to be about 500 times more potent than morphine in vivo. We have previously examined C9-alkenyl and hydroxyalkyl substituents in the N-phenethyl-5-(3-hydroxy)phenylmorphan class of compounds. Comparable C9-alkyl (methyl through butyl) substituents, with their sets of diastereomers, have not been explored. All these compounds have now been synthesized to determine the effect chain-length and stereochemistry at the C9 position in the molecule might have on their interaction with opioid receptors. We now report the synthesis and in vitro activity of 16 compounds, the C9-methyl, ethyl, propyl, and butyl diastereomers, using the inhibition of forskolin-induced cAMP accumulation assay. Several potent (sub-nanomolar and nanomolar) MOR compounds were found to be selective agonists with varying efficacy. Of greatest interest, a selective MOR antagonist was discovered; it did not display any DOR or KOR agonist activity in vitro, was three times more potent than naltrexone, and was found to antagonize the EC90 of fentanyl at MOR to a greater extent than naltrexone.
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影响因子：
11
作者：
Hedrick SL;Luo D;Kaska S;Niloy KK;Jackson K;Sarma R;Horn J;Baynard C;Leggas M;Butelman ER;Kreek MJ;Prisinzano TE
通讯作者：
Prisinzano TE
影响因子：
7.3
作者：
Hiebel, Anne-Cecile;Lee, Yong Sok;Rice, Kenner C.
通讯作者：
Rice, Kenner C.
影响因子：
2.7
作者：
Bender, Aaron M.;Clark, Mary J.;Mosberg, Henry I.
通讯作者：
Mosberg, Henry I.
影响因子：
7.3
作者：
Olson, Keith M.;Keresztes, Attila;Streicher, John M.
通讯作者：
Streicher, John M.
影响因子：
1.8
作者：
Linders, JTM;Flippen-Anderson, JL;Rice, KC
通讯作者：
Rice, KC