Received for publication February 5, 2007.
Revised March 27, 2007.
Accepted for publication April 23, 2007.

STRUCTURE-ACTIVITY RELATIONSHIP OF 1,4-DIHYDROPYRIDINES AS POTENTIATORS OF THE CFTR CHLORIDE CHANNEL

Abstract

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, like F508, give rise to a protein with both a defective maturation and altered channel gating. Mutations belonging to class III, like G551D and G1349D, cause only a gating defect. We have previously identified anti-hypertensive 1,4-dihydropyridines (DHPs), a class of drugs which block voltage-dependent Ca²⁺ channels, as effective potentiators of CFTR gating, able to correct the defective activity of CFTR mutants (Pedemonte et al., Mol Pharmacol 68: 1736-1746, 2005). However, optimization of potency for CFTR vs Ca²⁺ channels is required to design selective compounds for CFTR pharmacotherapy. In the present study, we have established DHP structure-activity relationship (SAR) 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 with a strong effect as potentiators on the F508, G551D, and G1349D CFTR mutants.

Key words: Ion channel regulation, Ion transporters (SERCA, Na/K ATPase, CFTR), Structure-activity relationships and modeling, Fluorescence techniques