JN403, in vitro characterization of a novel nicotinic acetylcholine receptor α7 selective agonist

This report describes the in vitro features of a novel selective nicotinic acetylcholine receptor (nAChR) alpha 7 agonist, JN403, (S)-(I-Azabicyclo[2.2.2]oct-3-yl)carbamic acid (S)- I -(2-fluoro-phenyl)-ethyl ester. JN403 was evaluated in a number of in vitro systems of different species, at recombinant receptors using radioligand binding, signal transduction and electrophysiological studies. When using [1251] alpha-bungarotoxin (alpha-BTX) as a radioligand, JN403 has high affinity for human recombinant nAChR 0 (pK(D) = 6.7). Functionally, JN403 is a partial and potent agonist at human nAChR alpha 7. The compound stimulates calcium influx in GH3 cells recombinantly expressing the human nAChR with an pEC(50) of 7.0 and an E-max. of 85% (compared to the full agonist epibatidine). In Xenopus oocytes expressing human nAChR 0 JN403 induces inward currents with an pEC50 of 5.7 and an E-max, of 55%. In both recombinant systems JN403 is a partial agonist and the agonistic effects are blocked after pre-administration of methyllycaconitine (MLA, 100 nM), a nAChR 0 antagonist. In functional calcium influx assays, JN403 displays a significantly lower potency for other subtypes of human nAChRs like alpha 4 beta 2, alpha 3 beta 4, alpha 1 p 1 gamma delta as well as 5HT(3) receptors when tested functionally as an antagonist (PIC50 < 4.8) and is devoid of agonistic activity (pEC50 < 4). Similarly, JN403 shows low binding activity at a wide panel of neurotransmitter receptors. Thus, JN403 is a potent and selective nAChR 0 agonist and will be a useful tool for the characterization of nAChR 0 mediated effects both in vitro and in vivo. (c) 2007 Elsevier Ireland Ltd. All rights reserved.