Froimowitz M, Cody V
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02178-9106.
Chirality. 1993;5(7):560-4. doi: 10.1002/chir.530050713.
A crystal of the potent opioid agonist ketobemidone [1-methyl-4-(3-hydroxyphenyl)-4-propionylipiperidine] HCl was analyzed by X-ray crystallography. The crystal was monoclinic, space group P2(1)/n with four molecules in the unit cell. In agreement with MM2 calculations (J. Med. Chem. 25:1127-1133, 1982), the crystal contains mirror image conformers in which the phenyl ring is equatorial to the piperidine ring. The conformers are enantiomers since they are not superimposable. One conformer is predicted to be responsible for the typical morphine-like activity of the compound since it closely matches the preferred conformer of the morphine-like (+)-phenylmorphan whereas the other conformer resembles the preferred conformers of (+)-beta-prodine and (-)-phenylmorphan which have atypical opioid properties and/or structure-activity relationships. The importance of considering the conformational enantiomers of a nonchiral receptor ligand in centrosymmetric crystal structures is emphasized.
采用X射线晶体学分析法对强效阿片类激动剂盐酸凯托米酮[1-甲基-4-(3-羟基苯基)-4-丙酰基哌啶]的晶体进行了分析。该晶体为单斜晶系，空间群为P2(1)/n，晶胞中有四个分子。与MM2计算结果（《药物化学杂志》25:1127 - 1133，1982年）一致，该晶体包含镜像构象异构体，其中苯环与哌啶环呈平伏键关系。这些构象异构体是对映体，因为它们不能相互叠合。预计其中一种构象异构体负责该化合物典型的吗啡样活性，因为它与吗啡样(+)-苯基吗啡烷的优选构象紧密匹配，而另一种构象异构体类似于(+)-β-丙哌啶和(-)-苯基吗啡烷的优选构象，它们具有非典型的阿片样性质和/或构效关系。强调了在中心对称晶体结构中考虑非手性受体配体的构象对映体的重要性。
