Timo Flessner

The Novel 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 Rodents

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.

Synthesis of Cephalostatin Analogues by Symmetrical and Non-Symmetrical Routes

The synthesis of the cephalostatin-analogous bis-steroidal pyrazines 6, 27a/b and 41 by the transformation of the C2-symmetrical diketone 6 as a central precursor, as well as the direct preparation of several non-symmetrical bis-steroidal pyrazines by coupling of enamino ketones (5, 40) with vinyl azides (17a/b) is reported. Furthermore, an improved procedure for preparation of the diketone 6 described earlier is presented.

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.