Novel TASK channels inhibitors derived from dihydropyrrolo[2,1-a] isoquinoline
Por:
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.
Publicada:
1 abr 2014
Resumen:
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 mu
M on TASK-1 and TASK-3, intermediate activity on TASK-1/TASK-3
heterodimer, moderate effect over hslo and TREK-1 (500 mu M), 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 mu M of these three compounds induced a
decrement by >39% of the TASK-carried leak current. Finally, only
compound 1 showed significant protection (similar to 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. (C) 2013 Elsevier Ltd. All rights
reserved.
Filiaciones:
Noriega-Navarro R.:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Quim Analit, Mexico City 04510, DF, Mexico
Departamento de Química Analítica, Facultad de Química, Ciudad Universitaria, México City 04510, Mexico
Lopez-Charcas O.:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neuropatol Mol, Div Neurociencias, Mexico City 04510, DF, Mexico
Departamento de Neuropatología Molecular, División de Neurociencias, Ciudad Universitaria, México City 04510, Mexico
Hernández-Enríquez B.:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neurodesarrollo & Fisiol, Div Neurociencias, Mexico City 04510, DF, Mexico
Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Ciudad Universitaria, México City 04510, Mexico
Reyes-Gutiérrez P.E.:
Departamento de Química Orgánica, Instituto de Química, Ciudad Universitaria, México City 04510, Mexico
Martínez R.:
Departamento de Química Orgánica, Instituto de Química, Ciudad Universitaria, México City 04510, Mexico
Landa A.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Microbiol & Parasitol, Mexico City 04510, DF, Mexico
Departamento de Microbiología y Parasitología, Facultad de Medicina, Ciudad Universitaria, México City 04510, Mexico
Morán J.:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neurodesarrollo & Fisiol, Div Neurociencias, Mexico City 04510, DF, Mexico
Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Ciudad Universitaria, México City 04510, Mexico
Gomora J.C.:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neuropatol Mol, Div Neurociencias, Mexico City 04510, DF, Mexico
Departamento de Neuropatología Molecular, División de Neurociencias, Ciudad Universitaria, México City 04510, Mexico
Garcia-Valdes J.:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Quim Analit, Mexico City 04510, DF, Mexico
Departamento de Química Analítica, Facultad de Química, Ciudad Universitaria, México City 04510, Mexico
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