Synthesis and enantioselectivity of the enantiomers of PG9 and SM21, new potent analgesic and cognition-enhancing drugs

✍ Scribed by M. Novella Romanelli; Alessandro Bartolini; Carlo Bertucci; Silvia Dei; Carla Ghelardini; M. Grazia Giovannini; Fulvio Gualtieri; Giancarlo Pepeu; Serena Scapecchi; Elisabetta Teodori

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 963 KB
• Volume: 8
• Category: Article
• ISSN: 0899-0042
• DOI: 10.1002/(sici)1520-636x(1996)8:3<225::aid-chir1>3.0.co;2-g

✦ Synopsis

The enantiomers of two a-tropanyl esters, SM,, (1) and PG, (2), derived from (+)-R-hyoscyamine, that act by increasing the central cholinergic tone, were obtained by esterification after resolution of the corresponding racemic acids [(-)-S-1, (-)-R-2 and(+)-S-2] and by stereospecific synthesis [(+)-R-ll. Their analgesic and cognition-enhancing activities were tested in mice and their ACh-releasing properties determined on rat parietal cortex. These compounds show enantioselectivity in analgesic and cognition-enhancing tests on mice, the eutomers being the isomers which possess the same spatial arrangement of the groups on the chiral atom as (+)-R hyoscyamine [(+)-R-SM,,, (+)-S-PG,]. The AChreleasing effect of the enantiomers of SM21 in rats is in agreement with the results in mice, while PG, enantiomers do not show any appreciable enantioselectivity in this test. On the basis of the different effects of the 5-HT4 antagonist SDZ 205557 on analgesia induced by the enantiomers of 1 and 2 and by (+)-R-hyoscyamine and the a-tropanyl ester of Z-phenylpropionic acid 3, a mechanism of action is proposed for this class of compounds.