THE SYNTHESIS AND SOME PHARMACOLOGICAL ACTIONS OF THE ENANTIOMERS OF THE K-CHANNEL BLOCKER CETIEDIL()

Cetiedil ((+/-)-2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1 H-azepin-1-yl) ethyl ester) possesses anti-sickling and analgesic, ant ispasmodic, local anaesthetic and vasodilator activities. A total synt hesis and circular dichroism spectra of the enantiomers of cetiedil is described, together with a comparison of their effectiveness as block ers of the Ca2+-activated K+ permeability of rabbit erythrocytes; the contractile response of intestinal smooth muscle to acetylcholine; the Ca2+-dependent contraction of depolarized intestinal muscle; and the cell volume-sensitive K+ permeability (K-vol) of liver cells. The enan tiomers did not differ substantially in their ability to block the Ca2 +-activated Kf permeability of rabbit red cells or in their effectiven ess as blockers of the contractile response of depolarized smooth musc le to externally applied Ca2+. There was a clear difference in the mus carinic blocking activity of the enantiomers, as assessed by inhibitio n of the contractile response of intestinal smooth muscle to acetylcho line; (+)-cetiedil was 7.7+/-0.2 (s.d.) times more active than the (-) form. The enantiomers also differed in their potency as blockers of t he increase in membrane conductance which occurs when liver cells swel l. The concentration of (+)-cetiedil needed to reduce the conductance increase by 50% was 2.04+/-0.54 (s.d.) mu M; (-)-cetiedil was 2.6+/-0. 8 (s.d.) times less active (IC50 of 5.2+/-1.2 mu M). Differences in th e biological actions of the enantiomers of cetiedil indicate that a mo re extensive study could be rewarding in relation to the use of the en antiomers both in therapeutics and in the study of Kf channels.