title: Pharmacological and behavioral profile of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141), a novel α7 nicotinic acetylcholine receptor agonist/serotonin 5-HT3 receptor antagonist.
abstract: OBJECTIVE
  Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT3 receptor (5-HT3R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects.
  
  
  RESULTS
  EVP-5141 bound to α7 nAChRs in rat brain membranes (K i  = 270 nM) and to recombinant human serotonin 5-HT3Rs (K i  = 880 nM) but had low affinity for α4β2 nAChRs (K i  > 100 μM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT3R antagonist but did not block α3β4, α4β2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3-30 mg kg(-1), p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3-3 mg kg(-1)) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg(-1), p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg(-1), i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg(-1), p.o.).
  
  
  CONCLUSIONS
  EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.
authors.affiliation: Pharma Research CNS, Bayer Healthcare AG, 42096, Wuppertal, Germany. frank.boess@t-online.de
authors.forename: Frank G
authors.initials: FG
authors.lastname: Boess
authors.forename: Jean
authors.initials: J
authors.lastname: de Vry
authors.forename: Christina
authors.initials: C
authors.lastname: Erb
authors.forename: Timo
authors.initials: T
authors.lastname: Flessner
authors.forename: Martin
authors.initials: M
authors.lastname: Hendrix
authors.forename: Joachim
authors.initials: J
authors.lastname: Luithle
authors.forename: Christoph
authors.initials: C
authors.lastname: Methfessel
authors.forename: Katrin
authors.initials: K
authors.lastname: Schnizler
authors.forename: F Josef
authors.initials: FJ
authors.lastname: van der Staay
authors.forename: Marja
authors.initials: M
authors.lastname: van Kampen
authors.forename: Welf-Burkhard
authors.initials: WB
authors.lastname: Wiese
authors.forename: Gerhard
authors.initials: G
authors.lastname: König
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018722:Nicotinic Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011812:Quinuclidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C585883:N-(1-azabicyclo(2.2.2)oct-3-yl)-6-quinolinecarboxamide; D018722:Nicotinic Agonists; D011804:Quinolines; D011812:Quinuclidines; D058831:Serotonin 5-HT3 Receptor Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor