Synthesis and pharmacological testing of dequalinium analogues as blockers of the apamin-sensitive Ca(2+)-activated K+ channel: variation of the length of the alkylene chain.
Dequalinium is a potent and selective blocker of the small conductance Ca(2+)-activated K+ (SKCa) channel in rat sympathetic neurones. Analogues of dequalinium possessing 3-6, 8, 10, and 12 methylene groups in the linking chain have been synthesized and tested for inhibition of the afterhyperpolarization in rat sympathetic neurones. The compounds having a 5-12-carbon chain showed very little variation in their activity as SKCa channel blockers. The analogues possessing four and three methylenes exhibited 3- and 8-fold lower potency, respectively, compared with dequalinium. These results are discussed in the context of possible modes of binding of the compounds to the SKCa channel.
Galanakis
D
D
Department of Chemistry, University College London, U.K.
Ganellin
C R
CR
Malik
S
S
Dunn
P M
PM
D000200:Action Potentials / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D001030:Apamin / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology*; D003868:Dequalinium / Q000138:chemical synthesis* / Q000494:pharmacology; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D026902:Potassium Channel Blockers; D051381:Rats; D013329:Structure-Activity Relationship
D026902:Potassium Channel Blockers; D001030:Apamin; D003868:Dequalinium; D002118:Calcium