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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 3 receptor (5-HT 3 R) 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 i  = 270 nM) and to recombinant human serotonin 5-HT 3 Rs ( 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-HT 3 R 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.

Rationale and objective: 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. Results: 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 super(-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 super(-1)) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg super(-1), p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg super(-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 super(-1), p.o.). Conclusions: 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.

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]

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-H[T.sub.3] receptor (5-H[T.sub.3]R) antagonist N-[(3R)-1azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP5141) and its behavioral effects. Results EVP-5141 bound to α7 nAChRs in rat brain membranes ([K.sub.i]=270 nM) and to recombinant human serotonin 5H[T.sub.3]Rs ([K.sub.i] = 880 nM) but had low affinity for α4β2 nAChRs ([K.sub.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-H[T.sub.3]R 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.sub.-1], p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP5141 may not share the abuse liability of nicotine. EVP5141 (0.3-3mg [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.). 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 Alzheimer's disease or schizophrenia. Keywords α7 nAChR agonist. Radioligand binding * Xenopus oocytes * Social recognition * Object recognition * Passive avoidance * Morris water maze * Working memory * Abuse liability * EVP-5141

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.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.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.).RESULTSEVP-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.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 Alzheimer's disease or schizophrenia.