KCNQ2/3 openers show differential selectivity and site of action across multiple KCNQ channels.

Autor: Zhang D; Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6118, USA. di.zhang@abbott.com, Thimmapaya R, Zhang XF, Anderson DJ, Baranowski JL, Scanio M, Perez-Medrano A, Peddi S, Wang Z, Patel JR, DeGoey DA, Gopalakrishnan M, Honore P, Yao BB, Surowy CS
Jazyk: angličtina
Zdroj: Journal of neuroscience methods [J Neurosci Methods] 2011 Aug 30; Vol. 200 (1), pp. 54-62. Date of Electronic Publication: 2011 Jun 23.
DOI: 10.1016/j.jneumeth.2011.06.014
Abstrakt: KCNQ2/3 voltage-gated potassium channels conduct low-threshold, slowly activating and non-inactivating currents to repolarize the neuronal resting membrane potential. The channels negatively regulate neuronal excitability and KCNQ2/3 openers are efficacious in hyperexcited states such as epilepsy and pain. We developed and utilized thallium influx assays to profile novel KCNQ2/3 channel openers with respect to selectivity across KCNQ subtypes and on requirement for tryptophan 236 of KCNQ2, a critical residue for activity of the KCNQ opener retigabine. Using distinct chemical series of openers, a quinazolinone series showed relatively poor selectivity across multiple KCNQ channels and lacked activity at the KCNQ2(W236L) mutant channel. In contrast, several novel benzimidazole openers showed selectivity for KCNQ2/3 and KCNQ2 and retain activity at KCNQ2(W236L). Profiling of several hundred KCNQ2/3 openers across multiple diverse chemical series revealed that openers show differential degrees of selectivity across subtypes, with selectivity most difficult to achieve against KCNQ2. In addition, we report the significant finding that KCNQ openers can pharmacologically differentiate between homomeric and heteromeric channels containing subtypes in common. Moreover, most openers assayed were dependent on the W236 for activity, whereas only a small number appear to use a distinct mechanism. Collectively, we provide novel insights into the molecular pharmacology of KCNQ channels by demonstrating differential selectivity and site of action for KCNQ2/3 openers. The high-throughput thallium influx assays should prove useful for rapid characterization of KCNQ openers and in guiding efforts to identify selective compounds for advancement towards the clinic.
(Copyright © 2011 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: