QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.107.034702v1 72/1/197    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pedemonte, N. Articles by Galietta, L. J. V. Search for Related Content PubMed PubMed Citation Articles by Pedemonte, N. Articles by Galietta, L. J. V.

Structure-Activity Relationship of 1,4-Dihydropyridines as Potentiators of the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel

Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy (N.P., R.R., L.J.V.G.); Centro di Biotecnologie Avanzate, Genova, Italy (N.P., L.J.V.G.); Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (D.B., O.M.); Dipartimento di Scienze Farmaceutiche, Università di Genova, Italy (M.G., M.M.)

Mutations occurring in the CFTR gene, encoding for the cystic fibrosis transmembrane conductance regulator chloride channel, cause cystic fibrosis (CF). Mutations belonging to class II, such as Phe508, give rise to a protein with both a defective maturation and altered channel gating. Mutations belonging to class III, such as G551D and G1349D, cause only a gating defect. We have previously identified antihypertensive 1,4-dihydropyridines (DHPs), a class of drugs that block voltage-dependent Ca²⁺ channels, as effective potentiators of CFTR gating, able to correct the defective activity of CFTR mutants (Mol Pharmacol 68:1736-1746, 2005). However, optimization of potency for CFTR versus Ca²⁺ channels is required to design selective compounds for CFTR pharmacotherapy. In the present study, we have established DHP structure-activity relationship for both CFTR potentiation and Ca²⁺ channel inhibition using cell-based assays for both types of channels. A panel of 333 felodipine analogs was studied to understand the effect of various substitutions and modifications in the DHP scaffold. Our results show that alkyl substitutions at the para position of the 4-phenyl ring lead to compounds with very low activity on Ca²⁺ channels and strong effect as potentiators on the Phe508, G551D, and G1349D CFTR mutants.

Address correspondence to: Luis J. V. Galietta, Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, L.go Gerolamo Gaslini 5, 16148 Genova, Italy. E-mail: galietta{at}unige.it