Stoiljkovic_2015_Biochem.Pharmacol_97(4)_576

Pharmacological activation of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) may improve cognition in schizophrenia and Alzheimer's disease. The present studies describe an integrated pharmacological analysis of the effects of FRM-17874, an analogue of encenicline, on alpha7 nAChRs in vitro and in behavioral and neurophysiological assays relevant to cognitive function. FRM-17874 demonstrated high affinity binding to human alpha7 nAChRs, displacing [(3)H]-methyllacaconitine (Ki=4.3nM). In Xenopus laevis oocytes expressing human alpha7 nAChRs, FRM-17874 acted as an agonist, evoking inward currents with an EC50 of 0.42muM. Lower concentrations of FRM-17874 (0.01-3nM) elicited no detectable current, but primed receptors to respond to sub-maximal concentrations of acetylcholine. FRM-17874 improved novel object recognition in rats, and enhanced memory acquisition and reversal learning in the mouse water T-maze. Neurophysiological correlates of cognitive effects of drug treatment, such as synaptic transmission, long-term potentiation, and hippocampal theta oscillation were also evaluated. Modulation of synaptic transmission and plasticity was observed in rat hippocampal slices at concentrations of 3.2 and 5nM. FRM-17874 showed a dose-dependent facilitation of stimulation-induced hippocampal theta oscillation in mice and rats. The FRM-17874 unbound brain concentration-response relationship for increased theta oscillation power was similar in both species, exhibited a biphasic pattern peaking around 3nM, and overlapped with active doses and exposures observed in cognition assays. In summary, behavioral and neurophysiological assays indicate a bell-shaped effective concentration range and this report represents the first attempt to explain the concentration-response function of alpha7 nAChR-mediated pro-cognitive effects in terms of receptor pharmacology.