Bibliographic Details
| 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-HT receptor antagonist. |
| Authors: |
Boess, Frank, Vry, Jean, Erb, Christina, Flessner, Timo, Hendrix, Martin, Luithle, Joachim, Methfessel, Christoph, Schnizler, Katrin, Staay, F., Kampen, Marja, Wiese, Welf-Burkhard, König, Gerhard |
| Source: |
Psychopharmacology. May2013, Vol. 227 Issue 1, p1-17. 17p. |
| Subjects: |
Nicotinic acetylcholine receptors, Pharmacology, Carboxamides, Scopolamine, Serotonin uptake inhibitors, Cognition disorders, Radioligand assay, Short-term memory |
| Abstract: |
Rationale and 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-HT receptor (5-HTR) antagonist N-[(3 R)-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 = 270 nM) and to recombinant human serotonin 5-HTRs ( K = 880 nM) but had low affinity for α4β2 nAChRs ( K > 100 μM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HTR 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, 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) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg, p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg, 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, 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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Psychology and Behavioral Sciences Collection |
