Synthesis and biological evaluation of 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide stereoisomers as novel positive allosteric modulators of sigma-1 receptor

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• 作者：Grigory Veinberg ; ^{veinberg@osi.lv} ; Maxim Vorona ; Liga Zvejniece ; Reinis Vilskersts ; Edijs Vavers ; Edvards Liepinsh ; Helena Kazoka ; Sergey Belyakov ; Anatoly Mishnev ; Jevgenijs Kuznecovs ; Sergejs Vikainis ; Natalja Orlova ; Anton Lebedev ; Yuri Ponomaryov ; Maija Dambrova
• 关键词：RKMJYPGOUBXWLP-GLGOKHISSA-N ; ZIZRQVWVGIHEIC-SCZZXKLOSA-N ; ZIZRQVWVGIHEIC-PSASIEDQSA-N ; ZIZRQVWVGIHEIC-WCBMZHEXSA-N ; YVJURLHORQGZMW-AAEUAGOBSA-N ; YVJURLHORQGZMW-YPMHNXCESA-N ; YVJURLHORQGZMW-DGCLKSJQSA-N ; YVJURLHORQGZMW-WCQYABFASA-N ; ZTGRWYMPQCQTHD-ONGXEEEL
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 May, 2013
• 年：2013
• 卷：21
• 期：10
• 页码：2764-2771
• 全文大小：869 K

文摘

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.