title: KCNQ2/3 openers show differential selectivity and site of action across multiple KCNQ channels.
abstract: 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.
authors: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6118, USA. di.zhang@abbott.com
authors: Di
authors: D
authors: Zhang
authors: Rama
authors: R
authors: Thimmapaya
authors: Xu-Feng
authors: XF
authors: Zhang
authors: David J
authors: DJ
authors: Anderson
authors: John L
authors: JL
authors: Baranowski
authors: Marc
authors: M
authors: Scanio
authors: Arturo
authors: A
authors: Perez-Medrano
authors: Sridhar
authors: S
authors: Peddi
authors: Zhi
authors: Z
authors: Wang
authors: Jyoti R
authors: JR
authors: Patel
authors: David A
authors: DA
authors: DeGoey
authors: Murali
authors: M
authors: Gopalakrishnan
authors: Prisca
authors: P
authors: Honore
authors: Betty B
authors: BB
authors: Yao
authors: Carol S
authors: CS
authors: Surowy
mesh_terms: D002219:Carbamates / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051659:KCNQ3 Potassium Channel / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009154:Mutation; D010655:Phenylenediamines / Q000494:pharmacology; D013793:Thallium / Q000493:pharmacokinetics*
chemical_list: D002219:Carbamates; D051656:KCNQ Potassium Channels; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; C117367:KCNQ4 protein, human; C412231:KCNQ5 protein, human; D010655:Phenylenediamines; C101866:ezogabine; D013793:Thallium