Bis-quinolinium cyclophanes: toward a pharmacophore model for the blockade of apamin-sensitive SKCa channels in sympathetic neurons.
The synthesis, pharmacological evaluation, and molecular modeling studies of unsymmetrical bis-alkylene bis-quinolinium cyclophanes and xylylene-alkylene bis-quinolinium cyclophanes is described. Two important structural features of the pharmacophore for SK(Ca) channel blockade have been identified. These are (i) an optimum distance of ca. 5.8A between the centroids of the pyridinium rings of the two quinolinium groups and (ii) a preference for conformations having the quinolinium groups in a synperiplanar orientation.
Galanakis
Dimitrios
D
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 541 24, Greece. dgalana@pharm.auth.gr
Ganellin
C Robin
CR
Chen
Jian-Quing
JQ
Gunasekera
Diyan
D
Dunn
Philip M
PM
D001030:Apamin / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D008956:Models, Chemical; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects*
D015220:Calcium Channels; D011804:Quinolines; D001030:Apamin