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, 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 Ca(2+)-activated K+ permeability of rabbit erythrocytes; the contractile response of intestinal smooth muscle to acetylcholine; the Ca(2+)-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 Ca(2+)-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 (-) from. 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.) microM; (-)-cetiedil was 2.6 +/- 0.8 (s.d.) times less active (IC50 of 5.2 +/- 1.2 microM). 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.
Department of Chemistry, University College London, UK.
C J
CJ
Roxburgh
C R
CR
Ganellin
M A
MA
Shiner
D C
DC
Benton
P M
PM
Dunn
Y
Y
Ayalew
D H
DH
Jenkinson
D000818:Animals; D000986:Antisickling Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers; D011817:Rabbits; D051381:Rats; D013237:Stereoisomerism
D000986:Antisickling Agents; D001381:Azepines; D026902:Potassium Channel Blockers; C006955:cetiedil