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 & Medicinal Chemistry
2013
G. Veinberg,
M. Vorona,
L. Zvejniece,
R. Vilskersts,
E. Vavers,
E. Liepinsh,
H. Kazoka,
Sergejs Beļakovs,
Anatolijs Mišņovs,
J. Kuznecovs,
S. Vikainis,
N. Orlova,
A. Lebedev,
J. Ponomarjov,
M. Dambrova
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.
Atslēgas vārdi
2-(5-Methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide; Enantiomers; Sigma-1 receptor; Agonist; Modulation
DOI
10.1016/j.bmc.2013.03.016
Hipersaite
http://www.sciencedirect.com/science/article/pii/S0968089613002290
Veinberg, G., Vorona, M., Zvejniece, L., Vilskersts, R., Vavers, E., Liepinsh, E., Kazoka, H., Beļakovs, S., Mišņovs, A., Kuznecovs, J., Vikainis, S., Orlova, N., Lebedev, A., Ponomarjov, J., 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 & Medicinal Chemistry, 2013, Vol.21, Iss.10, 2764.-2771.lpp. ISSN 0968-0896. Pieejams: doi:10.1016/j.bmc.2013.03.016
Publikācijas valoda
English (en)