Fragmentation of NS6740 molecular skeleton to investigate the alpha7 nicotinic acetylcholine receptor silent activation

NS6740 showed promising anti-inflammatory behavior by modulating alpha7 nicotinic acetylcholine receptors (1). The mechanism hypothesized is related to the ability of NS6740 to act as a “silent agonist”, stabilizing the desensitized states of the alpha7 receptor with little channel opening (2). This peculiar behavior was detected by using human α7 nAChRs expressed in Xenopus laevis oocytes and two-electrode voltage clamping. The drug and new analogs were tested at 10 μM, with an ACh post-control at 60 μM followed by the application of the positive allosteric modulator (PAM) PNU-120596 at 10 μM. The latter allowed confirmation that the application of NS6740 produced the desensitized state that could be rendered conductive by the application of the PAM (3). In this study, we focused on investigating the NS6740 pharmacophoric features required to produced alpha7 receptor activation and induction of the PAM-sensitive desensitized state. To this end, we planned the fragmentation of the NS6740 skeleton and we synthesized and analyzed the ability of each molecular portion to induce silent agonist activity (Figure 1). Figure 1: NS6740 molecular skeleton fragmentation Taken together, the electrophysiological data obtained with the newly synthesized fragments confirmed the crucial role of the positive ionizable group, the central hydrogen-bond acceptor heterocyclic moiety and the aromatic ring, as three structural requirements of the NS6740 scaffold to induce the alpha7 desensitized PAM-sensitive state. The synthesis and results of pharmacological investigation will be reported and discussed. (1) Papke, R.L.; Bagdas, D.; Kulkarni, A.R. et al. Neuropharmacology 2015, 91, 34-42. (2) Briggs, C.A.; Grønlien, J.H.; Curzon, P. et al. Br. J. Pharmacol. 2009, 158, 1486-494. (3) Papke, R.L.; Stokes, C. Methods 2010, 51, 121-133.