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Current Pharmaceutical Design

Author(s): Giuseppe Manfroni, Francesco Ragonese , Lorenzo Monarca, Andrea Astolfi, Loretta Mancinelli, Rossana G. Iannitti, Federica Bastioli, Maria L. Barreca, Violetta Cecchetti * and Bernard Fioretti*

DOI: 10.2174/1381612826666200316152645

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New Insights on KCa3.1 Channel Modulation

Page: [2096 - 2101] Pages: 6

  • * (Excluding Mailing and Handling)

Abstract

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.

Keywords: Intermediate conductance calcium activated potassium channel, KCa3.1, gating model, drug discovery, benzoimidazolones, 1-4 benzothiazine-3-one.

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