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RESEARCH PRODUCT

Investigation into Stereoselective Pharmacological Activity of Phenotropil

subject

description

Phenotropil (N-carbamoylmethyl-4-aryl-2-pyrrolidone (2-(2-oxo-4-phenyl-pyrrolidin-1-yl) acetamide; carphedon)) is clinically used in its racemic form as a nootropic drug that improves physical condition and cognition. The aim of this study was to compare the stereoselective pharmacological activity of R- and S-enantiomers of phenotropil in different behavioural tests. Racemic phenotropil and its enantiomers were tested for locomotor, antidepressant and memory-improving activity and influence on the central nervous system (CNS) using general pharmacological tests in mice. After a single administration, the amount of compound in brain tissue extracts was determined using an ultra performance liquid chromatography-tandem mass spectrometry (UPLC ⁄ MS ⁄ MS) method in a positive ion electrospray mode. In the open-field test, a significant increase in locomotor activity was observed after a single administration of R-phenotropil at doses of 10 and 50 mg ⁄ kg and S-pheno- tropil at a dose of 50 mg ⁄ kg. In the forced swim test, R-phenotropil induced an antidepressant effect at doses of 100 and 50 mg ⁄ kg, and S-phenotropil was active at a dose of 100 mg ⁄ kg. R-phenotropil significantly enhanced memory function in a passive avoidance response test at a dose of 1 mg ⁄ kg; the S-enantiomer did not show any activity in this test. However, the concentrations of R- and S-phenotropils in brain tissue were similar. In conclusion, the antidepressant and increased locomo- tor activity relies on both R- and S-phenotropils, but the memory-improving activity is only characteristic of R-phenotropil. These results may be important for the clinical use of optically pure isomers of phenotropil. Phenotropil (N-carbamoylmethyl-4-aryl-2-pyrrolidone (2-(2- oxo-4-phenyl-pyrrolidin-1-yl) acetamide; carphedon)) was discovered in Russia several decades ago as a nootropic drug that improves physical condition and cognition (1,2). Ini- tially, it was used on spaceships to increase the working capacities of cosmonauts, but during the last 10 years, phe- notropil has been introduced into clinical practice. The phe- notropil molecule contains one chiral centre in the 4th position of the pyrrolidone ring. Therefore, phenotropil can exist in two forms that share an enantiomeric relationship. The configuration of these two enantiomers has been desig- nated the 'R' and 'S' forms (fig. 1A,B).