Novel TASK channels inhibitors derived from dihydropyrrolo[2,1-a]isoquinoline.
TASK channels belong to the family of K(+) channels with 4 transmembrane segments and 2 pore domains (4TM/2P) per subunit. These channels have been related to apoptosis in cerebellar granule neurons (CGN), as well as cancer in other tissues. TASK current is regulated by hormones, neurotransmitters, anesthetics and divalent cations, which are not selective. Recently, there has been found some organic compounds that inhibit TASK current selectively. In order to find other modulators, we report here a group of five dihydropyrrolo[2,1-a]isoquinolines (DPIs), four of them with putative anticancer activity, that were evaluated on TASK-1 and TASK-3 channels. The compounds 1, 2 and 3 showed IC50 < 320 μM on TASK-1 and TASK-3, intermediate activity on TASK-1/TASK-3 heterodimer, moderate effect over hslo and TREK-1 (500 μM), and practically not inhibition on Shaker-IR, herg and IRK2.1 potassium channels, when they were expressed heterologously in Xenopus laevis oocytes. In rat CGN, 500 μM of these three compounds induced a decrement by >39% of the TASK-carried leak current. Finally, only compound 1 showed significant protection (∼36%) against apoptotic death of CGN induced by K(+) deprivation. These results suggest that DPI compounds could be potential candidates for designing new selective inhibitors of TASK channels.
['Noriega-Navarro|R|R|', 'Lopez-Charcas|O|O|', 'Hernández-Enríquez|B|B|', 'Reyes-Gutiérrez|P E|PE|', 'Martínez|R|R|', 'Landa|A|A|', 'Morán|J|J|', 'Gomora|J C|JC|', 'Garcia-Valdes|J|J|']
D000818:Animals D017209:Apoptosis D002478:Cells, Cultured D002531:Cerebellum D000072237:ERG1 Potassium Channel D051638:Ether-A-Go-Go Potassium Channels D007546:Isoquinolines D051379:Mice D015394:Molecular Structure D009419:Nerve Tissue Proteins D009474:Neurons D011188:Potassium D026902:Potassium Channel Blockers D024661:Potassium Channels, Inwardly Rectifying D024683:Potassium Channels, Tandem Pore Domain D024642:Potassium Channels, Voltage-Gated D011758:Pyrroles D051381:Rats D017208:Rats, Wistar D051637:Shaker Superfamily of Potassium Channels D014982:Xenopus laevis
TASK channels Dihydropyrrolo[2,1-a]isoquinoline Apoptosis DPI Leak channels