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

Abstract

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.

Differences in the actions of some blockers of the calcium‐activated potassium permeability in mammalian red cells

“…An action within the channel rather than at either its inner or outer surface seems more probable, particularly in view of our ®ndings (i) that quaternization of cetiedil greatly reduces its activity (Benton et al, 1994), and (ii) that the action of cetiedil and of hydroxy cetiedil (UCL 1269), a less lipophilic derivative of cetiedil, increased with the period of preincubation with the cells (Figure 1). The observation (Roxburgh et al, 1996) that the enantiomers of cetiedil are equi-active as blockers of the Ga rdos channel also suggests that the lipophilicity of the molecule is more important that its shape as a determinant of activity. However, in recent studies with more potent analogues of cetiedil, we have obtained evidence that structural features can also play a role To summarize to this point, the evidence suggests that cetiedil and its congeners either act at or aect the K + binding sites within the channel that determine its selectivity.…”

“…The recent cloning and sequencing by Ishii et al (1997) of a human intermediate conductance Ca 2+ -activated K + channel with the properties of the Ga rdos channel has shown it to be structurally related to, but distinct from, the SK Ca subtype. This erythrocyte Ca 2+ -activated K + permeability (P K(Ca) ) has been known for some years to be blocked by quinine and quinidine (Armando-Hardy et al, 1975;Reichstein & Rothstein, 1981), carbocyanine dyes (Simons, 1979), cetiedil (Berkowitz & Orringer, 1982, 1984Christophersen & Vestgergaard-Bogind, 1985;Roxburgh et al, 1996) and charybdotoxin (Wol et al, 1988;Brugnara et al, 1993a) though not by apamin (Burgess et al, 1981; for additional references see Schwarz & Passow, 1983;Sarkadi & Ga rdos, 1985). More recently, nifedipine (Kaji, 1990), nitrendipine (Ellory et al, 1992) and clotrimazole (Alvarez et al, 1992;Brugnara et al, 1993b) have also been shown to be potent inhibitors.…”

Modulators of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels and their Therapeutic Indications

“…(3)): the chiral center, the 3-thienyl group and the ester functionality with a two carbon chain while keeping the cyclic tertiary amine in the seven membered aliphatic ring constant. The two enantiomers showed similar activity in blocking erythrocyte KCa3.1 demonstrating that chirality was not important [227]. The thienyl group could be replaced by phenyl without any change in activity showing that the presence of the S atom was not required.…”

Synthesis and Structure−Activity Relationships of Cetiedil Analogues as Blockers of the Ca2+-Activated K+Permeability of Erythrocytes

“…It is argued that cetiedil's ability to reduce the loss of K + from the cells may diminish the reduction in cell volume that can trigger the sickling of erythrocytes (see refs and for reviews). Cetiedil is also of interest because it blocks other K + channels that are involved in cell volume regulation in hepatocytes 28 and lymphocytes. , As part of a broader investigation of the medicinal chemistry of nonpeptidic K + channel blocking agents, − we have initiated a study of the structure−activity relationships and mechanism of action , of cetiedil and its congeners as inhibitors of the Ca 2+ -activated K + permeability in mammalian erythrocytes. Our aims are to characterize the pharmacophore for cetiedil and to develop more potent and selective blockers of the intermediate conductance Ca 2+ -activated K + channel.…”