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 opening K+ channels in the cell membrane, the K+ channel openers. The enantiomers 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 of the K+ channel opener [3H]P1075 in strips of rat aorta with pKi values 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 diminished under depolarized conditions (KCl = 55 mmol/l). Both compounds increased the permeability of the cell membrane for K+ as suggested by their ability to stimulate 86Rb+ efflux from rat aortic strips. The vasorelaxant and the 86Rb+ 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) enantiomer 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.
Quast
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Sandoz Pharma Ltd., Basel, Switzerland.
Villhauer
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D000758:Anesthesia; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D004730:Endothelium, Vascular / Q000502:physiology; D006146:Guanidines / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012414:Rubidium Radioisotopes; D013237:Stereoisomerism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents; D019806:Cromakalim; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D009638:Norepinephrine