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
Bioorganic and Medicinal Chemistry
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.
2-(5-Methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide; Enantiomers; Sigma-1 receptor; Agonist; Modulation
Veinberg, G., Vorona, M., Zvejniece, L., Vilkersts, R., Vavers, E., Liepiņš, E., Kazoka, H., Beļakovs, S., Mišņovs, A., Kuznecovs, J., Vikainis, S., Orlova, N., Lebedev, A., Ponomaryov, Y., Dambrova, M. 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. Bioorganic and Medicinal Chemistry, 2013, Vol.21, Iss.10, pp.2764-2771. ISSN 0968-0896. Available from: doi:10.1016/j.bmc.2013.03.016