Pharmacological and behavioral profile of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141), a novel [alpha]7 nicotinic acetylcholine receptor agonist/serotonin 5-HT^sub 3^ receptor antagonist

• Published in: Psychopharmacology Vol. 227; no. 1; p. 1
• Main Authors: Boess, Frank G, de Vry, Jean, Erb, Christina, Flessner, Timo, Hendrix, Martin, Luithle, Joachim, Methfessel, Christoph, Schnizler, Katrin, van der Staay, F Josef, van Kampen, Marja, Wiese, Welf-burkhard, König, Gerhard
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Nature B.V 01.05.2013
• Subjects: Antagonist drugs; Drug therapy; Psychopharmacology; Serotonin
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-012-2933-4

Agonists of [alpha]7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel [alpha]7 nAChR agonist/serotonin 5-HT^sub 3^ receptor (5-HT^sub 3^R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects. EVP-5141 bound to [alpha]7 nAChRs in rat brain membranes (K ^sub i^=270 nM) and to recombinant human serotonin 5-HT^sub 3^Rs (K ^sub i^=880 nM) but had low affinity for [alpha]4[beta]2 nAChRs (K ^sub i^>100 [mu]M). EVP-5141 was a potent agonist at recombinant rat and human [alpha]7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT^sub 3^R antagonist but did not block [alpha]3[beta]4, [alpha]4[beta]2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3-30 mg kg^sup -1^, p.o.), suggesting that the nicotine cue is not mediated by the [alpha]7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3-3 mg kg^sup -1^) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg^sup -1^, p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg^sup -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^sup -1^, p.o.). EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that [alpha]7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.[PUBLICATION ABSTRACT]