EVP-6124, a novel and selective ¦Á7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of ¦Á7 nicotinic acetylcholine receptors

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• 作者：Jos Prickaerts^b ; ¹ ; ^{jos.prickaerts@maastrichtuniversity.nl} ; Nick P. van Goethem^b ; ¹ ; ^{n.vangoethem@maastrichtuniversity.nl} ; Richard Chesworth^a ; ² ; ^{Rchesworth@epizyme.com} ; Gideon Shapiro^c ; ^{gshapiro@envivopharma.com} ; Frank G. Boess^d ; ³ ; ^{Frank.Boess@t-online.de} ; Christoph Methfessel^e ; ⁴ ; ^{chrismet@t-online.de} ; Olga A.H. Reneerkens^b ; ^{o.reneerkens@maastrichtuniversity.nl} ; Dorothy G. Flood^a ; ^{dflood@envivopharma.com} ; Dana Hilt^a ; ^{dhilt@envivopharma.com} ; Maria Gawryl^a ; ^{mgawryl@envivopharma.com} ; Sonia Bertrand^f ; ^{sonia.bertrand@hiqscreen.com} ; Daniel Bertrand^f ; ^{daniel.bertrand@hiqscreen.com} ; Gerhard Kö ; nig^a ; ^{gkoenig@envivopharma.com}
• 关键词：¦Á7 nAChR ; Object recognition task ; Memory ; Partial agonist ; Novel mechanism of action ; Acetylcholine esterase inhibitor
• 刊名：Neuropharmacology
• 出版年：2012
• 出版时间：February 2012
• 年：2012
• 卷：62
• 期：2
• 页码：1099-1110
• 全文大小：820 K

文摘

EVP-6124, (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, is a novel partial agonist of ¦Á7 neuronal nicotinic acetylcholine receptors (nAChRs) that was evaluated here in?vitro and in?vivo. In binding and functional experiments, EVP-6124 showed selectivity for ¦Á7 nAChRs and did not activate or inhibit heteromeric ¦Á4¦Â2 nAChRs. EVP-6124 had good brain penetration and an adequate exposure time. EVP-6124 (0.3?mg/kg, p.o.) significantly restored memory function in scopolamine-treated rats (0.1?mg/kg, i.p.) in an object recognition task (ORT). Although donepezil at 0.1?mg/kg, p.o. or EVP-6124 at 0.03?mg/kg, p.o. did not improve memory in this task, co-administration of these sub-efficacious doses fully restored memory. In a natural forgetting test, an ORT with a 24?h retention time, EVP-6124 improved memory at 0.3?mg/kg, p.o. This improvement was blocked by the selective ¦Á7 nAChR antagonist methyllycaconitine (0.3?mg/kg, i.p. or 10?¦Ìg, i.c.v.). In co-application experiments of EVP-6124 with acetylcholine, sustained exposure to EVP-6124 in functional investigations in oocytes caused desensitization at concentrations greater than 3?nM, while lower concentrations (0.3-1?nM) caused an increase in the acetylcholine-evoked response. These actions were interpreted as representing a co-agonist activity of EVP-6124 with acetylcholine on ¦Á7 nAChRs. The concentrations of EVP-6124 that resulted in physiological potentiation were consistent with the free drug concentrations in brain that improved memory performance in the ORT. These data suggest that the selective partial agonist EVP-6124 improves memory performance by potentiating the acetylcholine response of ¦Á7 nAChRs and support new therapeutic strategies for the treatment of cognitive impairment.

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