Details

Autor(en) / Beteiligte

• Roxburgh, Craig J.
• Ganellin, C. Robin
• Shiner, Mark A. R.
• Benton, David C. H.
• Dunn, Philip M.
• Ayalew, Yeshi
• Jenkinson, Donald H.

Titel

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

Ist Teil von

• Journal of pharmacy and pharmacology, 1996-08, Vol.48 (8), p.851-859

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

1996

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.