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Novel Negative Gating Modulators of KCa2/3 as Pharmacological Tools for Novel Treatments
Author(s) -
OlivánViguera Aida,
Valero Marta,
Badorrey Ramón,
Wulff Heike,
Köhler Ralf
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.943.2
Subject(s) - gating , in vivo , pharmacophore , pharmacology , chemistry , potency , electrical impedance myography , ex vivo , neuroscience , medicine , in vitro , biology , vasodilation , biochemistry , microbiology and biotechnology
KCa2/3 channels are present in many organs and tissues such as vascular endothelia, intestinal and bronchial epithelia, neurons or blood cell lineages. Therefore, they play important roles in cardiovascular, immunological and neurological functions and emerge as therapeutic targets. Existing KCa2/3 pore blockers, due to its mechanism of action, could exert unspecific blocking effects at high dosages. Negative‐gating modulators, which modulates the regulatory mechanism of the active channel, seem to be better pharmacological tools. Methods We synthesized new small molecules and performed patch‐clamp experiments to evaluate their potency. We also evaluated their functional activity by isometric tension myography on porcine coronary arteries. We determined cardiovascular safety and efficacy by telemetric cardiovascular monitoring on mice. Results Our novel entities met Lipinski's rule of five and we identified RA‐2 as KCa2/3 pan‐negative gating modulator, with potencies in the nM range and with no considerable effects on distantly related human K channels. RA‐2 blocks EDH‐type relaxation and it is apparently safe in‐vivo, with no effects in blood pressure, although it moderately reduces heart rate. Discussion We identified new molecules that could serve as pharmacophores for structurally new chemical entities for specific negative‐gating modulation of KCa2/3. RA‐2 has nanomolar potency, and ex‐vivo and in‐vivo activity, and it could be a tool to study physiological and pathophysiological roles of the KCa2/3 channels and may be of therapeutic utility.