Novel positive allosteric modulators of sigma-1 receptor represented by 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide enantiomers were synthesised using an asymmetric Michael addition of 2-nitroprop-1-enylbenzene to diethyl malonate. Following the chromatographic separation of the methyl erythro- and threo-4-nitro-3R- and 3S-phenylpentanoate diastereoisomers, target compounds were obtained by their reductive cyclisation into 5-methyl-4-phenylpyrrolidin-2-one enantiomers and the attachment of the acetamide group to the heterocyclic nitrogen. Experiments with electrically stimulated rat vas deference contractions induced by the PRE-084, an agonist of sigma-1 receptor, showed that (4R,5S)- and (4R,5R)-2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamides with an R-configuration at the C-4 chiral centre in the 2-pyrrolidone ring were more effective positive allosteric modulators of sigma-1 receptor than were their optical antipodes.

使用 2-硝基丙-1-烯基苯与二乙基苯的不对称迈克尔加成合成了以 2-(5-甲基-4-苯基-2-氧代吡咯烷-1-基)-乙酰胺对映体为代表的新型 sigma-1 受体正变构调节剂丙二酸。色谱分离甲基赤式和苏式-4-硝基-3R-和3S-苯基戊酸酯非对映异构体后，通过还原环化成5-甲基-4-苯基吡咯烷-2-酮对映体并连接得到目标化合物乙酰胺基团变为杂环氮。由 sigma-1 受体激动剂 PRE-084 诱导的电刺激大鼠输精管收缩实验表明 (4 R ,5 S )- 和 (4 R ,5 R )-2-(5-methyl-4在2-吡咯烷酮环的C-4手性中心具有R-构型的-苯基-2-氧代吡咯烷-1-基)-乙酰胺是比其光学对映体更有效的sigma-1受体正变构调节剂。