title: 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.
abstract: EVP-6124, (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, is a novel partial agonist of α7 neuronal nicotinic acetylcholine receptors (nAChRs) that was evaluated here in vitro and in vivo. In binding and functional experiments, EVP-6124 showed selectivity for α7 nAChRs and did not activate or inhibit heteromeric α4β2 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 α7 nAChR antagonist methyllycaconitine (0.3 mg/kg, i.p. or 10 μg, 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 α7 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 α7 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'.
authors.affiliation: Maastricht University, School for Mental Health and Neuroscience, 6200 MD Maastricht, The Netherlands. jos.prickaerts@maastrichtuniversity.nl
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
authors.forename: Nick P
authors.initials: NP
authors.lastname: van Goethem
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
authors.forename: Gideon
authors.initials: G
authors.lastname: Shapiro
authors.forename: Frank G
authors.initials: FG
authors.lastname: Boess
authors.forename: Christoph
authors.initials: C
authors.lastname: Methfessel
authors.forename: Olga A H
authors.initials: OA
authors.lastname: Reneerkens
authors.forename: Dorothy G
authors.initials: DG
authors.lastname: Flood
authors.forename: Dana
authors.initials: D
authors.lastname: Hilt
authors.forename: Maria
authors.initials: M
authors.lastname: Gawryl
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.forename: Gerhard
authors.initials: G
authors.lastname: König
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D007189:Indans / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C573817:7-chloro-N-quinuclidin-3-yl-benzo(b)thiophene-2-carboxamide; D002800:Cholinesterase Inhibitors; C579165:Chrna7 protein, rat; D007189:Indans; D018722:Nicotinic Agonists; D010880:Piperidines; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077265:Donepezil