Department of Anesthesiology

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Molecular switch for CLC-K Cl- channel block/activation: optimal pharmacophoric requirements towards high-affinity ligands.

TitleMolecular switch for CLC-K Cl- channel block/activation: optimal pharmacophoric requirements towards high-affinity ligands.
Publication TypeJournal Article
Year of Publication2008
AuthorsLiantonio A, Picollo A, Carbonara G, Fracchiolla G, Tortorella P, Loiodice F, Laghezza A, Babini E, Zifarelli G, Pusch M, Camerino DConte
JournalProc Natl Acad Sci U S A
Volume105
Issue4
Pagination1369-73
Date Published2008 Jan 29
ISSN1091-6490
KeywordsAnimals, Benzofurans, Binding, Competitive, Chloride Channels, Humans, Ligands, Niflumic Acid, Patch-Clamp Techniques, Protein Isoforms, Rats, Xenopus laevis
Abstract

ClC-Ka and ClC-Kb Cl(-) channels are pivotal for renal salt reabsorption and water balance. There is growing interest in identifying ligands that allow pharmacological interventions aimed to modulate their activity. Starting from available ligands, we followed a rational chemical strategy, accompanied by computational modeling and electrophysiological techniques, to identify the molecular requisites for binding to a blocking or to an activating binding site on ClC-Ka. The major molecular determinant that distinguishes activators from blockers is the level of planarity of the aromatic portions of the molecules: only molecules with perfectly coplanar aromatic groups display potentiating activity. Combining several molecular features of various CLC-K ligands, we discovered that phenyl-benzofuran carboxylic acid derivatives yield the most potent ClC-Ka inhibitors so far described (affinity <10 microM). The increase in affinity compared with 3-phenyl-2-p-chlorophenoxy-propionic acid (3-phenyl-CPP) stems primarily from the conformational constraint provided by the phenyl-benzofuran ring. Several other key structural elements for high blocking potency were identified through a detailed structure-activity relationship study. Surprisingly, some benzofuran-based drugs inhibit ClC-Kb with a similar affinity of <10 microM, thus representing the first inhibitors for this CLC-K isoform identified so far. Based on our data, we established a pharmacophore model that will be useful for the development of drugs targeting CLC-K channels.

DOI10.1073/pnas.0708977105
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID18216243
PubMed Central IDPMC2234145
Grant ListGGP04018 / / Telethon / Italy