title: Novel TASK channels inhibitors derived from dihydropyrrolo[2,1-a]isoquinoline.
abstract: 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.
authors.affiliation: Departamento de Química Analítica, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico.
authors.forename: R
authors.initials: R
authors.lastname: Noriega-Navarro
authors.affiliation: Departamento de Neuropatología Molecular, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico.
authors.forename: O
authors.initials: O
authors.lastname: Lopez-Charcas
authors.affiliation: Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico.
authors.forename: B
authors.initials: B
authors.lastname: Hernández-Enríquez
authors.affiliation: Departamento de Química Orgánica, Instituto de Química, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico.
authors.forename: P E
authors.initials: PE
authors.lastname: Reyes-Gutiérrez
authors.affiliation: Departamento de Química Orgánica, Instituto de Química, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico.
authors.forename: R
authors.initials: R
authors.lastname: Martínez
authors.affiliation: Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico.
authors.forename: A
authors.initials: A
authors.lastname: Landa
authors.affiliation: Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico.
authors.forename: J
authors.initials: J
authors.lastname: Morán
authors.affiliation: Departamento de Neuropatología Molecular, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico.
authors.forename: J C
authors.initials: JC
authors.lastname: Gomora
authors.affiliation: Departamento de Química Analítica, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico. Electronic address: jesusgv@unam.mx.
authors.forename: J
authors.initials: J
authors.lastname: Garcia-Valdes
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051637:Shaker Superfamily of Potassium Channels / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007546:Isoquinolines; C407082:Kcnk9 protein, rat; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D024683:Potassium Channels, Tandem Pore Domain; D024642:Potassium Channels, Voltage-Gated; D011758:Pyrroles; D051637:Shaker Superfamily of Potassium Channels; C000593095:dihydropyrrolo(2,1-a)isoquinoline; C420132:potassium channel subfamily K member 3; D011188:Potassium
keywords: Apoptosis; DPI; Dihydropyrrolo[2,1-a]isoquinoline; Leak channels; TASK channels