ABCMdb

PMID: 19880323

Cateni F, Zacchigna M, Pedemonte N, Galietta LJ, Mazzei MT, Fossa P, Giampieri M, Mazzei M
Synthesis of 4-thiophen-2'-yl-1,4-dihydropyridines as potentiators of the CFTR chloride channel.
Bioorg Med Chem. 2009 Dec 1;17(23):7894-903. Epub 2009 Oct 20., 2009-12-01 [PubMed]

Sentences

No. Mutations Sentence Comment

14 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp For instance, deletion of phenylalanine at position 508 (DF508), the most frequent mutation (occurring in more than 50-70% of patients),5 causes both a severe CFTR processing defect (the protein being trapped and degraded at the endoplasmic [ER] level) and a decrease of its channel activity.6-8 Other mutations, like G551D and G1349D, produce only a gating defect. Login to comment 18 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp In this regard, we have found that the 1,4-dihydropyridines (DHPs) used to treat hypertension are acting as potentiators and so are able to stimulate the activity of some CFTR mutants (in particular, G551D, G1349D and rescued DF508-CFTR).14,15 Antihypertensive DHPs act by blocking L-type voltage-dependent Ca2+ channels (L-VDCC) and therefore cause the relaxation of arterial 0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. Login to comment 233 ABCC7 p.Gly551Asp In particular, potentiators may be useful to enhance the activity of the DF508 mutant, once the trafficking defect is corrected, at least partially, by suitable pharmacological chaperones.23,24 In 2005, we showed that DHPs possess a notable activity in potentiating the conductance in cells carrying CFTR gating mutants as G551D or when the cells with DF508-CFTR were rescued by incubation at low temperature.11 In this way more than 300 DHPs with a phenyl group in position 4 were evaluated in order to investigate the structure-activity relationship. Login to comment