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BEHAVIORAL PHARMACOLOGY
7 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 RodentsPharma Research CNS (F.G.B., J.D.V., C.E., F.-J.v.d.S., M.v.K., G.K.), Medicinal Chemistry (T.F., M.H., J.L., B.R.), Bayer HealthCare AG, Wuppertal, Germany; Bayer Crop Science, Monheim, Germany (W.B.W.); and Bayer Technology Services GmbH Biophysics, Leverkusen, Germany (C.M., K.S.)
The relative contribution of 
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2, 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 7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide (ABBF). ABBF bound to 7 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 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 34, 42, 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 7 nAChR antagonist methyllycaconitine at 10 µg, indicating that it is mediated by 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 7 nAChR and that selective 7 nAChR agonists may not share the abuse liability of nicotine. Our results support the hypothesis that 7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits with low abuse potential.
Address correspondence to: Dr. Gerhard Koenig, EnVivo Pharmaceuticals; 480 Arsenal Street, Watertown, MA 02472. E-mail: gkoenig{at}envivopharma.com
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