Your browser doesn't support javascript.
loading
Pharmacological Characterization of the Novel and Selective α7 Nicotinic Acetylcholine Receptor-Positive Allosteric Modulator BNC375.
Wang, Xiaohai; Daley, Christopher; Gakhar, Vanita; Lange, Henry S; Vardigan, Joshua D; Pearson, Michelle; Zhou, Xiaoping; Warren, Lee; Miller, Corin O; Belden, Michelle; Harvey, Andrew J; Grishin, Anton A; Coles, Carolyn J; O'Connor, Susan M; Thomson, Fiona; Duffy, Joseph L; Bell, Ian M; Uslaner, Jason M.
Afiliación
  • Wang X; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.) xiaohai_wang@merck.com.
  • Daley C; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Gakhar V; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Lange HS; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Vardigan JD; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Pearson M; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Zhou X; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Warren L; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Miller CO; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Belden M; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Harvey AJ; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Grishin AA; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Coles CJ; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • O'Connor SM; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Thomson F; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Duffy JL; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Bell IM; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
  • Uslaner JM; Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.).
J Pharmacol Exp Ther ; 373(2): 311-324, 2020 05.
Article en En | MEDLINE | ID: mdl-32094294
Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Bencetonio / Clorobencenos / Receptor Nicotínico de Acetilcolina alfa 7 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Pharmacol Exp Ther Año: 2020 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Bencetonio / Clorobencenos / Receptor Nicotínico de Acetilcolina alfa 7 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Pharmacol Exp Ther Año: 2020 Tipo del documento: Article