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
| Autor: | Christina Erb, Marja Van Kampen, Welf-Burkhard Wiese, Frank G. Boess, Jean De Vry, Gerhard Konig, Christoph Methfessel, Katrin Schnizler, Joachim Luithle, F. Josef van der Staay, Timo Flessner, Martin Hendrix |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Agonist Quinuclidines alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class Morris water navigation task Pharmacology Nicotine Mice Xenopus laevis 5-HT3 Receptor Antagonist Memory Avoidance Learning medicine Animals Humans Serotonin 5-HT3 Receptor Antagonists Inverse agonist Nicotinic Agonists Rats Wistar Dose-Response Relationship Drug Chemistry Antagonist Rats Mice Inbred C57BL HEK293 Cells Nicotinic agonist Quinolines Female Endogenous agonist Protein Binding medicine.drug |
| Zdroj: | Psychopharmacology, 227, 1. Springer Verlag |
| ISSN: | 1432-2072 0033-3158 |
| Popis: | 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. 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.). 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. |
| Databáze: | OpenAIRE |
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