EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors

NEUROPHARMACOLOGY

卷:62

Article

Prickaerts, Jos²  van Goethem, Nick P.²  Chesworth, Richard¹  Shapiro, Gideon³  Boess, Frank G.⁴  Methfessel, Christoph⁵  Reneerkens, Olga A. H.²  Flood, Dorothy G.¹  Hilt, Dana¹  Gawryl, Maria¹  Bertrand, Sonia⁶  Bertrand, Daniel⁶  Koenig, Gerhard¹ 

[1] EnVivo Pharmaceut Inc, Watertown, MA 02472 USA

[2] Maastricht Univ, Sch Mental Hlth & Neurosci, NL-6200 MD Maastricht, Netherlands

[3] EnVivo Pharmaceut Inc, Gainesville, FL USA

[4] Bayer HealthCare, Pharma Res CNS, D-42096 Wuppertal, Germany

[5] Bayer Technol Serv GmbH, D-51368 Leverkusen, Germany

[6] HiQScreen Sarl, CH-1211 Geneva 12, Switzerland

关键词: alpha 7 nAChR;    Object recognition task;    Memory;    Partial agonist;    Novel mechanism of action;    Acetylcholine esterase inhibitor;   

DOI  :  10.1016/j.neuropharm.2011.10.024

来源: Elsevier

【 摘 要 】

EVP-6124, (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, is a novel partial agonist of alpha 7 neuronal nicotinic acetylcholine receptors (nAChRs) that was evaluated here in vitro and in vivo. In binding and functional experiments, EVP-6124 showed selectivity for alpha 7 nAChRs and did not activate or inhibit heteromeric alpha 4 beta 2 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 alpha 7 nAChR antagonist methyllycaconitine (0.3 mg/kg, i.p. or 10 mu g, 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 alpha 7 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 alpha 7 nAChRs and support new therapeutic strategies for the treatment of cognitive impairment. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. (C) 2011 Elsevier Ltd. All rights reserved.

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