Tritylamino aromatic heterocycles and related carbinols as blockers of ca 2+-activated potassium ion channels underlying neuronal hyperpolarization.
A series of novel aromatic tritylamino heterocycles has been synthesized and the compounds have been tested in comparison with clotrimazole for their ability to inhibit the slow afterhyperpolarization current (sI (AHP)) in cultured rat hippocampal pyramidal neurones. Some analogues of the clotrimazole metabolite, 2-chlorophenyl-diphenyl methanol, having different chlorination substitution in the triphenyl group have also been examined. Two compounds in particular, 3-[(2-chlorophenyl)-diphenylmethylamino] pyridine (3a, UCL 1880) and 2-tritylaminothiazole (6, UCL 2027), are of special interest; they are effective blockers of the sI (AHP) (IC (50) = 1.1-1.2 microM) and are much more selective than clotrimazole since they have less effect on the high voltage-activated Ca2+ current.
Department of Chemistry, University College London, 20 Gordon Street, UK.
Patricia A
PA
Zunszain
Mala M
MM
Shah
Zena
Z
Miscony
Mazyar
M
Javadzadeh-Tabatabaie
Dennis G
DG
Haylett
C Robin
CR
Ganellin
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003022:Clotrimazole / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis*; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D024681:Potassium Channels, Calcium-Activated; D003022:Clotrimazole