SYNTHESIS AND ENANTIOSELECTIVITY OF THE ENANTIOMERS OF PG(9) AND SM(21), NEW POTENT ANALGESIC AND COGNITION-ENHANCING DRUGS

The enantiomers of two alpha-tropanyl esters, SM(21) (1) and PG(9) (2) , derived from (+)-R-hyoscyamine, that act by increasing the central c holinergic tone, were obtained by esterification after resolution of t he corresponding racemic acids [(-)-S-1, (-)-R-2 and (+)-S-2] and by s tereospecific synthesis [(+)-R-1]. Their analgesic and cognition-enhan cing activities were tested in mice and their ACh-releasing properties determined on rat parietal cortex. These compounds show enantioselect ivity in analgesic and cognition-enhancing tests on mice, the eutomers being the isomers which possess the same spatial arrangement of the g roups on the chiral atom as (+)-R hyoscyamine [(+)-R-SM(21), (+)-S-PG( 9)]. The ACh-releasing effect of the enantiomers of SM,, in rats is in agreement with the results in mice, while PG(9) enantiomers do not sh ow any appreciable enantioselectivity in this test. On the basis of th e different effects of the 5-HT4 antagonist SDZ 205557 on analgesia in duced by the enantiomers of 1 and 2 and by (+)-R-hyoscyamine and the a lpha-tropanyl ester of 2-phenylpropionic acid 3, a mechanism of action is proposed for this class of compounds. (C) 1996 Wiley-Liss, Inc.