The Synthesis and Some Pharmacological Actions of the Enantiomers of the K+-Channel Blocker Cetiedil

Abstract

Abstract Cetiedil ((±)-2−cyclohexyl-2-(3−thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1−yl) ethyl ester) possesses anti-sickling and analgesic, antispasmodic, local anaesthetic and vasodilator activities. A total synthesis and circular dichroism spectra of the enantiomers of cetiedil is described, together with a comparison of their effectiveness as blockers 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 (Kvol) of liver cells. The enantiomers did not differ substantially in their ability to block the Ca2+-activated K+ permeability of rabbit red cells or in their effectiveness as blockers of the contractile response of depolarized smooth muscle to externally applied Ca2+. There was a clear difference in the muscarinic blocking activity of the enantiomers, as assessed by inhibition of the contractile response of intestinal smooth muscle to acetylcholine; (+)-cetiedil was 7.7 ± 0.2 (s.d.) times more active than the (–-) form. The enantiomers also differed in their potency as blockers of the increase in membrane conductance which occurs when liver cells swell. The concentration of (+)-cetiedil needed to reduce the conductance increase by 50% was 2.04 ± 0.54 (s.d.) μM; (–-)-cetiedil was 2.6 ± 0.8 (s.d.) times less active (IC50 of 5.2 ± 1.2 μM). Differences in the biological actions of the enantiomers of cetiedil indicate that a more extensive study could be rewarding in relation to the use of the enantiomers both in therapeutics and in the study of K+ channels.