Benzothiazepine CGP37157 and its 2′-isopropyl analogue modulate Ca2+ entry through CALHM1

• There are no efficient pharmacological tools to study the Ca2+ channel CALHM1.
• We discovered the benzothiazapine CGP37157 blocks CALHM1 at low concentrations.
• 4,1-benzothiazepines are the first family of organic compounds modulating CALHM1.
• The S-enantiomer of a new derivative of CGP, ITH12575, blocked CALHM1 at 1 μM.

CALHM1 is a Ca2+ channel discovered in 2008, which plays a key role in the neuronal electrical activity, among other functions. However, there are no known efficient blockers able to modulate its Ca2+ handling ability. We herein describe that benzothiazepine CGP37157 and its newly synthesized analogue ITH12575 reduced Ca2+ influx through CALHM1 at low micromolar concentrations. These results could serve as a starting point for the development of more selective CALHM1 ligands using CGP37157 as a hit compound, which would help to study the physiological role of CALHM1 in the control of [Ca2+]cyt in excitable cells, as well as its implication in CNS diseases.

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