4-Chlorobenzo[F]isoquinoline (CBIQ), a novel activator of CFTR and DeltaF508 CFTR.
4-Chlorobenzo[F]isoquinoline (CBIQ) is a novel compound, here shown to activate both CFTR (cystic fibrosis transmembrane conductance regulator) Cl- ion channels and KCNN4, intermediate conductance, calcium-sensitive K+-channels, present in transporting epithelia by the use of heterologous expression systems. Earlier studies with other benzoquinolines, namely 7,8- and 5,6 benzoquinoline, showed they too could activate CFTR and KCNN4, but the evidence was only indirect. However this study also shows that CBIQ can also activate DeltaF508 CFTR, the most common mutant form of CFTR present in approximately 75% of patients with cystic fibrosis. This property is not shared with the other benzoquinolines. As activation of CFTR and KCNN4 work in unison to promote epithelial chloride secretion, CBIQ is a new chemical scaffold for developing agents that may be useful in cystic fibrosis.
Murthy
Meena
M
Department of Medicine (Level 5, Box 157), University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
Pedemonte
Nicoletta
N
MacVinish
Lesley
L
Galietta
Luis
L
Cuthbert
Alan
A
D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D007546:Isoquinolines / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010618:Phenanthrolines / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D014982:Xenopus laevis
C495450:4-chlorobenzo(f)isoquinoline; C505032:CFTR protein, human; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D007546:Isoquinolines; C496923:KCNN4 protein, human; D010618:Phenanthrolines; D024681:Potassium Channels, Calcium-Activated; D011804:Quinolines; D018075:RNA, Complementary; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C117298:7,8-benzoquinoline