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. 2022 Sep 30;27(19):6455. doi: 10.3390/molecules27196455.
Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.
四组非对映异构的 C9-烯基 5-苯基吗啡烷，其 C9-烯基链的长度各不相同，旨在研究这些空间上不同的配体对阿片受体的影响。通过福斯高林诱导的 cAMP 积累测定获得了功能活性，并用 [S]GTPgS 测定法和呼吸抑制测定法对几种化合物进行了检测。在这四组化合物中，根据其 C9-烯基链的长度以及最重要的立体化学，观察到了相似和不同之处。发现三种 MOR 拮抗剂与纳曲酮一样或更有效，与纳曲酮不同的是，它们都没有 MOR、KOR 或 DOR 激动剂活性。获得了几种有效的 MOR 完全激动剂，并且发现了特别有趣的部分激动剂，其引起的呼吸抑制比吗啡引起的呼吸抑制要小。还使用分子建模探索了立体化学和 C9-烯基链长度的影响。发现 MOR 拮抗剂与非活性（4DKL）MOR 晶体结构相互作用，而激动剂与活性（6DDF）MOR 晶体结构相互作用。比较它们在小鼠 MOR 上的结合模式，有助于深入了解其立体化学诱导的药理学差异的结构基础。
