Joachim Luithle

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

Rationale and objectiveAgonists 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.ResultsEVP-5141 bound to α7 nAChRs in rat brain membranes (Kiu2009=u2009270xa0nM) and to recombinant human serotonin 5-HT3Rs (Kiu2009=u2009880xa0nM) but had low affinity for α4β2 nAChRs (Kiu2009>u2009100xa0μM). 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 (0.3–30xa0mg 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 (0.3–3xa0mg kg−1) improved performance in the rat social recognition test. EVP-5141 (0.3xa0mg kg−1, p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1xa0mg 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 (0.3xa0mg kg−1, p.o.).ConclusionsEVP-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 Alzheimers disease or schizophrenia.

Pharmacological and behavioral profile of EVP-5141, a novel α7 nicotinic acetylcholine receptor agonist

Background: Agonists at a7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. Methods: The effect of the novel a7 nAChR agonist EVP-5141 on a4b2 and a7 nAChR in rat brain membranes was determined using [H]cytisine and [H]methyllycaconitine binding assays. Affinity at recombinant human 5-HT3 receptor expressed in HEK293 cells was measured in [H]GR65630 binding assays. The functional potency and selectivity of EVP-5141 was determined in electrophysiological assays using recombinant a7, a3b4, a4b2 and muscle nAChRs and 5HT3 receptors expressed in Xenopus oocytes. Subsequently the effects of EVP5141 in drug discrimination and several tests of learning and memory were determined. Results: EVP-5141 bound to a7 nAChR in rat brain membranes (Ki 1⁄4 270 nM) and to recombinant human 5-HT3 receptors (Ki 1⁄4 880 nM), but had low affinity for a4b2 nAChRs (Ki > 100 mM). EVP-5141 was a potent agonist at the recombinant rat and human a7 nAChR, but did not show agonist activity at the 5-HT3 receptor and no or weak agonist activity at the other nAChR subtypes tested. EVP-5141 acted as an antagonist of the 5HT3 receptor but did not block a3b4, a4b2 and muscle nAChR. Rats trained to discriminate nicotine (0.4 mg/kg, s.c.) 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 a7 nAChR and that selective a7 nAChR agonists may not share the abuse liability of nicotine. Performance in the rat social recognition test was improved after administration of 0.3-3 mg/kg EVP-5141. EVP-5141 (0.3 mg/kg p.o.) antagonized scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg/kg, i.p.) improved spatial working memory of aged rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object (0.3 mg/kg p.o.) and social recognition memory in mice (0.001 3 mg/kg). Conclusions: EVP-5141 improved performance in several learning and memory tests in both rats and mice supporting the hypothesis that a7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Schizophrenia and Alzheimer’s Disease.