THE INDIVIDUAL ENANTIOMERS OF CIS-CROMAKALIM POSSESS K+ CHANNEL OPENING ACTIVITY

Cromakalim (BRL 34915), a racemic trans-3,4-disubstituted benzopyran, is the prototype of a novel group of vasorelaxants which act by openin g K+ channels in the cell membrane, the K+ channel openers. The enanti omers of cis-cromakalim were synthesized and their biological activity compared to that of the enantiomers of (trans-)cromakalim. Both the ( +)-(3R,4R) enantiomer and its (-)-(3S,4S) antipode inhibited binding o f the K+ channel opener [H-3]P1075 in strips of rat aorta with pK(i) v alues of 5.4 and 5.2, respectively. They relaxed noradrenaline-induced contractions of rat isolated aorta under control conditions with pD2 values of 5.7 and 5.2; their vasorelaxant potency was greatly diminish ed under depolarized conditions (KCl = 55 mmol/l). Both compounds incr eased the permeability of the cell membrane for K+ as suggested by the ir ability to stimulate Rb-86(+) efflux from rat aortic strips. The va sorelaxant and the R-86(+) efflux-stimulating effects of the compounds were inhibited by the sulfonylurea, glibenclamide. These results show that the enantiomers of cis-cromakalim are genuine K+ channel openers . The (R,R) enantiomer is 50 times weaker than the (-)-(3S,4R) enantio mer of cromakalim (= levcromakalim, BRL 38227) but 3 times more potent than the (+)-(3R,4S) enantiomer. These data highlight the importance of the stereochemistry at both the 3 and 4 position of the benzopyran ring.