Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone Street, Lexington, KY 40536, USA.
Molecules. 2023 Jul 14;28(14):5411. doi: 10.3390/molecules28145411.
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 -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.
5-(3-羟基)苯基吗啡喃结构类化合物与经典吗啡喃、4,5-环氧吗啡喃和 6,7-苯并吗啡喃不同，它们的芳环呈赤道取向，而不是经典阿片类药物中环的轴向取向。这种经过修饰和简化的类阿片结构已被证明保留了抗伤害感受活性，这取决于其立体化学和取代基，其中一些化合物的效力比吗啡强得多。我们发现，简单的 C9-羟基-5-(3-羟基)苯基吗啡喃对映体在体内的效力比吗啡强约 500 倍。我们之前研究了 -苯乙基-5-(3-羟基)苯基吗啡喃类化合物中 C9-烯基和羟烷基取代基。尚未探索具有相同的 C9-烷基（甲基至丁基）取代基及其非对映异构体。现在已经合成了所有这些化合物，以确定分子中 C9 位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 16 种化合物的合成和体外活性，这些化合物是 C9-甲基、乙基、丙基和丁基非对映异构体，使用抑制福司可林诱导的 cAMP 积累测定法。发现几种具有强效（亚纳摩尔和纳摩尔）MOR 化合物的化合物是具有不同效力的选择性激动剂。最有趣的是，发现了一种选择性 MOR 拮抗剂；它在体外没有显示任何 DOR 或 KOR 激动剂活性，比纳曲酮强三倍，并且发现它在 MOR 上拮抗芬太尼的 EC90 的程度大于纳曲酮。
