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.

Agonists at α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. The effect of the novel α7 nAChR agonist EVP-5141 on α4β2 and α7 nAChR in rat brain membranes was determined using [3H]cytisine and [3H]methyllycaconitine binding assays. Affinity at recombinant human 5-HT3 receptor expressed in HEK293 cells was measured in [3H]GR65630 binding assays. The functional potency and selectivity of EVP-5141 was determined in electrophysiological assays using recombinant α7, α3β4, α4β2 and muscle nAChRs and 5-HT3 receptors expressed in Xenopus oocytes. Subsequently the effects of EVP-5141 in drug discrimination and several tests of learning and memory were determined. EVP-5141 bound to α7 nAChR in rat brain membranes (Ki = 270 nM) and to recombinant human 5-HT3 receptors (Ki = 880 nM), but had low affinity for α4β2 nAChRs (Ki > 100 μM). EVP-5141 was a potent agonist at the recombinant rat and human α7 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 5-HT3 receptor but did not block α3β4, α4β2 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 α7 nAChR and that selective α7 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). 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 Schizophrenia and Alzheimer's Disease.

The present study investigated the putative pro-cognitive effects of the novel selective PDE9 inhibitor BAY 73-6691. The effects on basal synaptic transmission and long-term potentiation (LTP) were investigated in rat hippocampal slices. Pro-cognitive effects were assessed in a series of learning and memory tasks using rodents as subjects. BAY 73-6691 had no effect on basal synaptic transmission in hippocampal slices prepared from young adult (7- to 8-week-old) Wistar rats. A dose of 10 microM, but not 30 microM, BAY 73-6691 enhanced early LTP after weak tetanic stimulation. The dose effective in young adult Wistar rats did not affect LTP in hippocampal slices prepared from young (7- to 8-week-old) Fischer 344 X Brown Norway (FBNF1) rats, probably reflecting strain differences. However, it increased basal synaptic transmission and enhanced early LTP after weak tetanic stimulation in hippocampal slices prepared from very old (31- to 35-month-old) FBNF1 rats. BAY 73-6691 enhanced acquisition, consolidation, and retention of long-term memory (LTM) in a social recognition task and tended to enhance LTM in an object recognition task. Bay 73-6691 attenuated the scoplamine-induced retention deficit in a passive avoidance task, and the MK-801-induced short-term memory deficits in a T-maze alternation task. The mechanism of action, possibly through modulation of the NO/cGMP-PKG/CREB pathway, is discussed. Our findings support the notion that PDE9 inhibition may be a novel target for treating memory deficits that are associated with aging and neurodegenerative disorders such as Alzheimer's disease.

The relative contribution of α4β2, α7 and other nicotinic acetylcholine receptor (nAChR) subtypes to the memory enhancing versus the addictive effects of nicotine is the subject of ongoing debate. In the present study, we characterized the pharmacological and behavioral properties of the α7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide (ABBF). ABBF bound to α7 nAChR in rat brain membranes (Ki = 62 nM) and to recombinant human 5-hydroxytryptamine (5-HT)3 receptors (Ki = 60 nM). ABBF was a potent agonist at the recombinant rat and human α7 nAChR expressed in Xenopus oocytes, but it did not show agonist activity at other nAChR subtypes. ABBF acted as an antagonist of the 5-HT3 receptor and α3β4, α4β2, and muscle nAChRs (at higher concentrations). ABBF improved social recognition memory in rats (0.3–1 mg/kg p.o.). This improvement was blocked by intracerebroventricular administration of the α7 nAChR antagonist methyllycaconitine at 10 μg, indicating that it is mediated by α7 nAChR agonism. In addition, ABBF improved working memory of aged rats in a water maze repeated acquisition paradigm (1 mg/kg p.o.) and object recognition memory in mice (0.3–1 mg/kg p.o.). Rats trained to discriminate nicotine (0.4 mg/kg s.c.) from vehicle did not generalize to ABBF (0.3–30 mg/kg p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that selective α7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.