title: Synthesis and pharmacological testing of polyaminoquinolines as blockers of the apamin-sensitive Ca2+-activated K+ channel (SK(Ca)).
abstract: The synthesis and pharmacological testing of a series of non-peptidic blockers of the SK(Ca) (SK-3) channel is described. Target compounds were designed to mimic the spatial relationships of selected key residues in the energy-minimised structure of the octadecapeptide apamin, which are a highly potent blocker of this channel. Structures consist of a central unit, either a fumaric acid or an aromatic ring, to which are attached two alkylguanidine or two to four alkylaminoquinoline substituents. Potency was tested by the ability to inhibit the SK(Ca) channel-mediated after-hyperpolarization (AHP) in cultured rat sympathetic neurones. It was found that bis-aminoquinoline derivatives are significantly more potent as channel blockers than are the corresponding guanidines. This adds to the earlier evidence that delocalisation of positive charge through the more extensive aminoquinolinium ring system is important for effective channel binding. It was also found that an increase in activity can be gained by the addition of a third aminoquinoline residue to give non-quaternized amines which have submicromolar potencies (IC(50)=0.13-0.36 microM). Extension to four aminoquinoline residues increased the potency to IC(50)=93 nM.
authors.affiliation: Department of Chemistry, University College London, 20, Gordon Street, London WC1H 0AJ, UK.
authors.forename: David I
authors.initials: DI
authors.lastname: Fletcher
authors.forename: C Robin
authors.initials: CR
authors.lastname: Ganellin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.forename: Philip M
authors.initials: PM
authors.lastname: Dunn
authors.forename: Donald H
authors.initials: DH
authors.lastname: Jenkinson
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001030:Apamin / Q000737:chemistry / Q000494:pharmacology*; D019791:Guanidine / Q000737:chemistry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D046509:Tissue Culture Techniques
chemical_list: D000634:Aminoquinolines; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D001030:Apamin; D019791:Guanidine