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

• Published in: Neuropharmacology 2015-08, Vol.95, p.503-510
• Main Authors: Moreno-Ortega, Ana J., Martínez-Sanz, Francisco J., Lajarín-Cuesta, Rocío, de los Rios, Cristóbal, Cano-Abad, María F.
• Format: Article
• Language: English
• Subjects: Benzothiazepines; Calcium - metabolism; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium homeostasis modulator 1 (CALHM1); Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone - pharmacology; Cations - metabolism; CGP37157; Clonazepam - analogs & derivatives; Clonazepam - chemistry; Clonazepam - pharmacology; Cobalt - metabolism; Dose-Response Relationship, Drug; HeLa Cells; Humans; Indoles - pharmacology; ITH12575; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Neurodegenerative diseases; Polymorphism, Genetic; Proton Ionophores - pharmacology; Thiazepines - chemical synthesis; Thiazepines - chemistry; Thiazepines - pharmacology; Transfection
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.02.016

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. [Display omitted] •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.