Pharmacovigilance database search discloses ClC-K channels as a novel target of the AT1receptor blockers valsartan and olmesartan.
Human ClC-K chloride channels are highly attractive targets for drug discovery as they have a variety of important physiological functions and are associated with genetic disorders. These channels are crucial in the kidney as they control chloride reabsorption and water diuresis. In addition, loss-of-function mutations of CLCNKB and BSND genes cause Bartter's syndrome (BS), whereas CLCNKA and CLCNKB gain-of-function polymorphisms predispose to a rare form of salt sensitive hypertension. Both disorders lack a personalized therapy that is in most cases only symptomatic. The aim of this study was to identify novel ClC-K ligands from drugs already on the market, by exploiting the pharmacological side activity of drug molecules available from the FDA Adverse Effects Reporting System database.



We searched for drugs having a Bartter-like syndrome as a reported side effect, with the assumption that BS could be causatively related to the block of ClC-K channels. The ability of the selected BS-causing drugs to bind and block ClC-K channels was then validated through an integrated experimental and computational approach based on patch clamp electrophysiology in HEK293 cells and molecular docking simulations.



Valsartan and olmesartan were able to block ClC-Ka channels and the molecular requirements for effective inhibition of these channels have been identified.



These results suggest additional mechanisms of action for these sartans further to their primary AT1receptor antagonism and propose these compounds as leads for designing new potent ClC-K ligands.
Department of Pharmacy - Drug Sciences, University of Bari 'Aldo Moro', Bari, Italy.
Paola
P
Imbrici
Department of Pharmacy - Drug Sciences, University of Bari 'Aldo Moro', Bari, Italy.
Domenico
D
Tricarico
Department of Pharmacy - Drug Sciences, University of Bari 'Aldo Moro', Bari, Italy.
Giuseppe Felice
GF
Mangiatordi
Department of Pharmacy - Drug Sciences, University of Bari 'Aldo Moro', Bari, Italy.
Orazio
O
Nicolotti
Department of Pharmacy - Drug Sciences, University of Bari 'Aldo Moro', Bari, Italy.
Marcello Diego
MD
Lograno
Department of Pharmacy - Drug Sciences, University of Bari 'Aldo Moro', Bari, Italy.
Diana
D
Conte
Department of Pharmacy - Drug Sciences, University of Bari 'Aldo Moro', Bari, Italy.
Antonella
A
Liantonio
D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology*; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D060735:Pharmacovigilance; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*; D000068756:Valsartan / Q000737:chemistry / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D018118:Chloride Channels; D007093:Imidazoles; D013777:Tetrazoles; D000068756:Valsartan; C437965:olmesartan