Novel TASK channels inhibitors derived from dihydropyrrolo[2,1-a]isoquinoline

• Published in: Neuropharmacology Vol. 79; pp. 28 - 36
• Main Authors: Noriega-Navarro, R., Lopez-Charcas, O., Hernández-Enríquez, B., Reyes-Gutiérrez, P.E., Martínez, R., Landa, A., Morán, J., Gomora, J.C., Garcia-Valdes, J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2014
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Cells, Cultured; Cerebellum - drug effects; Cerebellum - physiology; Dihydropyrrolo[2,1-a]isoquinoline; DPI; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - metabolism; Isoquinolines - chemistry; Isoquinolines - pharmacology; Leak channels; Mice; Molecular Structure; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurons - physiology; Potassium - metabolism; Potassium Channel Blockers - chemistry; Potassium Channel Blockers - pharmacology; Potassium Channels, Inwardly Rectifying - metabolism; Potassium Channels, Tandem Pore Domain - antagonists & inhibitors; Potassium Channels, Tandem Pore Domain - genetics; Potassium Channels, Tandem Pore Domain - metabolism; Potassium Channels, Voltage-Gated - metabolism; Pyrroles - chemistry; Pyrroles - pharmacology; Rats; Rats, Wistar; Shaker Superfamily of Potassium Channels - metabolism; TASK channels; Xenopus laevis; DPI; Leak channels; TASK channels; Dihydropyrrolo[2,1-a]isoquinoline; Apoptosis
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.10.028

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. •Three dihydropyrroloisoquinolines (DPIs) inhibited TASK channels.•DPI compounds (100 μM) did not inhibit significantly other K+ channels.•These compounds inhibited IKso currents in cerebellar granule neurons (CGN).•One of these compounds protected against K+-dependent programmed cell death in CGN.