The novel α7 nicotinic acetylcholine receptor agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide improves working and recognition memory in rodents

The relative contribution of alpha 4 beta 2, alpha 7 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 alpha 7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1benzofuran- 2-carboxamide (ABBF). ABBF bound to alpha 7 nAChR in rat brain membranes (K-i = 62 nM) and to recombinant human 5-hydroxytryptamine (5-HT)(3) receptors (K-i = 60 nM). ABBF was a potent agonist at the recombinant rat and human alpha 7 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 alpha 3 beta 4, alpha 4 beta 2, 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 alpha 7 nAChR antagonist methyllycaconitine at 10 mu g, indicating that it is mediated by alpha 7 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 alpha 7 nAChR and that selective alpha 7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that alpha 7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.