Giuseppe Manfroni, Francesco Ragonese , Lorenzo Monarca, Andrea Astolfi, Loretta Mancinelli, Rossana G. Iannitti, Federica Bastioli, Maria L. Barreca, Violetta Cecchetti * and Bernard Fioretti* Pages 2096 - 2101 ( 6 )
The human intermediate conductance calcium-activated potassium channel, KCa3.1, is involved in several pathophysiological conditions playing a critical role in cell secretory machinery and calcium signalling. The recent cryo-EM analysis provides new insights for understanding the modulation by both endogenous and pharmacological agents. A typical feature of this channel is the low open probability in saturating calcium concentrations and its modulation by potassium channel openers (KCOs), such as benzo imidazolone 1-EBIO, without changing calcium-dependent activation. In this paper, we proposed a model of KCOs action in the modulation of channel activity. The KCa3.1 channel has a very rich pharmacological profile with several classes of molecules that selectively interact with different binding sites of the channel. Among them, benzo imidazolones can be openers (positive modulators such as 1-EBIO, DC-EBIO) or blockers (negative modulators such as NS1619). Through computation modelling techniques, we identified the 1,4-benzothiazin-3-one as a promising scaffold to develop new KCa3.1 channel modulators. Further studies are needed to explore the potential use of 1-4 benzothiazine- 3-one in KCa3.1 modulation and its pharmacological application.
Intermediate conductance calcium activated potassium channel, KCa3.1, gating model, drug discovery, benzoimidazolones, 1-4 benzothiazine-3-one.
Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1-06123-Perugia (PG), Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1-06123-Perugia (PG), Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, S&R Farmaceutici S.p.A Bastia Umbra, 08063 Perugia, S&R Farmaceutici S.p.A Bastia Umbra, 08063 Perugia, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1-06123-Perugia (PG), Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1-06123-Perugia (PG), Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via Elce di Sotto 8, 06123 Perugia