title: Synthesis, SAR, crystal structure, and biological evaluation of benzoquinoliziniums as activators of wild-type and mutant cystic fibrosis transmembrane conductance regulator channels.
abstract: Chloride channels play important roles in homeostasis and regulate cell volume, transepithelial transport, and electrical excitability. Despite recent progress made in the genetic and molecular aspect of chloride channels, their pharmacology is still poorly understood. The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated epithelial chloride channel for which mutations cause cystic fibrosis. Here we have synthesized benzo[c]quinolizinium and benzo[f]indolo[2,3-a]quinolizinium salts (MPB) and performed a SAR to identify the structural basis for activation of the CFTR chloride channel. Synthesized compounds were evaluated on wild-type CFTR and on CFTR having the glycine-to-aspartic acid missense mutation at codon 551 (G551D-CFTR), using a robot and cell-based assay. The presence of an hydroxyl group at position 6 of the benzo[c]quinolizinium skeleton associated with a chlorine atom at position 10 or 7 and an alkyl chain at position 5 determined the highest activity. The most potent product is 5-butyl-7-chloro-6-hydroxybenzo[c]quinolizinium chloride (8u, MPB-104). 8u is 100 times more potent than the parent compound 8a (MPB-07).
authors.affiliation: Laboratoire de Chimie Organique, Faculté de Médecine et de Pharmacie, Université de Poitiers, 34 rue du Jardin des Plantes, BP 199, 86005 Poitiers Cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Marivingt-Mounir
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
authors.forename: Renaud
authors.initials: R
authors.lastname: Dérand
authors.forename: Laurence
authors.initials: L
authors.lastname: Bulteau-Pignoux
authors.forename: Dung
authors.initials: D
authors.lastname: Nguyen-Huy
authors.forename: Bernard
authors.initials: B
authors.lastname: Viossat
authors.forename: Georges
authors.initials: G
authors.lastname: Morgant
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vierfond
authors.forename: Yvette
authors.initials: Y
authors.lastname: Mettey
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C483198:5-butyl-7-chloro-6-hydroxybenzo(c)quinolizinium; D011807:Quinolizines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator