Loew G H, Berkowitz D S
J Med Chem. 1979 Jun;22(6):603-7. doi: 10.1021/jm00192a001.
A conformational study of a series of oripavine derivatives is reported using the PCILO semiempirical quantum mechanical method. Low-energy conformers of carbinol substituents on C7-C19-R1R2OH are found with and without intramolecular hydrogen bonding to the C6-OCH3 group. The relative energies of these conformers depend on the R1 and R2 groups and the diastereoisomerism of the alcohol. The results are consistent with available NMR and IR studies of intramolecular hydrogen bonding and with crystallographic data. The importance of interaction between specific conformations of C19 carbinols and a lipophilic receptor site is suggested. A hypothesis is formulated to explain observed differences in pharmacological activity between diastereoisomers at C19 in the oripavine series and also to explain how these diastereoisomers alter the established pattern of N-substituent effects on relative agonist/antagonist potency found in other rigid opiates. By contrast, conformational studies of the C19 optical isomers of the C7-C8 etheno form of buprenorphine lead to the prediction of greatly reduced intrinsic potency differences between C19 diastereoisomers for this compound and for buprenorphine itself.
本文报道了利用PCILO半经验量子力学方法对一系列东罂粟碱衍生物进行的构象研究。研究发现，在有或没有与C6 - OCH3基团形成分子内氢键的情况下，C7 - C19 - R1R2OH上的甲醇取代基均存在低能量构象。这些构象的相对能量取决于R1和R2基团以及醇的非对映异构现象。研究结果与现有的关于分子内氢键的核磁共振（NMR）和红外光谱（IR）研究以及晶体学数据一致。研究表明了C19甲醇特定构象与亲脂性受体位点之间相互作用的重要性。本文提出了一个假设，以解释东罂粟碱系列中C19处非对映异构体在药理活性上观察到的差异，同时也解释了这些非对映异构体如何改变在其他刚性阿片类药物中发现的N - 取代基对相对激动剂/拮抗剂效力影响的既定模式。相比之下，对丁丙诺啡C7 - C8乙烯形式的C19光学异构体的构象研究预测，该化合物以及丁丙诺啡本身的C19非对映异构体之间的内在效力差异将大大降低。
