Henkel J G, Berg E P, Portoghese P S
J Med Chem. 1976 Nov;19(11):1308-14. doi: 10.1021/jm00233a011.
The synthesis of racemic threo- and erythro-5-methylmethadone (3a and 3b, respectively) was carried out and the solution conformation of each isomer was investigated through pKa and NMR studies. The data indicate that 3a-HCl exists exclusively in an internally hydrogen-bonded conformation while the erythro isomer 3b-HCl is present as a mixture of conformations. The erythro racemate 3b was found to possess 5.4 times the analgetic potency of (+/-)-methadone in contrast to the threo racemate 3a which was inactive and devoid of antagonist activity. The fact that the inactive racemate 3a contains the 5S,6R stereoisomer, which combines the configurations found in the more active enantiomers of methadone and isomethadone, suggests that the chiral centers do not behave as independent units and that conformational factors are playing an important role in governing stereoselectivity. These results, when analyzed together with earlier reports, suggest that one of the pharmacophoric conformations of the diphenylpropylamine analgetics possesses an antiperiplanar-like disposition of the Ph2CCOEt and +NHMe2 groups.
外消旋苏型和赤型5-甲基美沙酮（分别为3a和3b）的合成得以进行，并通过pKa和核磁共振研究对每种异构体的溶液构象进行了考察。数据表明，3a - HCl仅以分子内氢键构象存在，而赤型异构体3b - HCl则以构象混合物的形式存在。已发现赤型外消旋体3b的镇痛效力是(±)-美沙酮的5.4倍，与之形成对比的是，苏型外消旋体3a无活性且没有拮抗活性。无活性的外消旋体3a含有5S,6R立体异构体，该异构体结合了在美沙酮和异美沙酮活性更高的对映体中发现的构型，这一事实表明手性中心并非独立起作用，构象因素在决定立体选择性方面起着重要作用。这些结果与早期报告一起分析时表明，二苯基丙胺类镇痛药的药效构象之一具有Ph2CCOEt和 +NHMe2基团的反式共平面样排列。
