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NEUROPHARMACOLOGY

Effect of Novel Negative Allosteric Modulators of Neuronal Nicotinic Receptors on Cells Expressing Native and Recombinant Nicotinic Receptors: Implications for Drug Discovery

Divisions of Pharmacology (T.F.G.-C., B.J.H., S.B.M., R.A.E., D.B.M.) and Medicinal Chemistry and Pharmacognosy (R.E.P., C.L.), College of Pharmacy, The Ohio State University, Columbus, Ohio; Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, Columbus, Ohio (R.T.B., M.X.Z.); and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio (A.B.P., C.M.O., D.D.R., S.C.B.)

Allosteric modulation of nAChRs is considered to be one of the most promising approaches for drug design targeting nicotinic acetylcholine receptors (nAChRs). We have reported previously on the pharmacological activity of several compounds that seem to act noncompetitively to inhibit the activation of 3β4^* nAChRs. In this study, the effects of 51 structurally similar molecules on native and recombinant 3β4 nAChRs are characterized. These 51 molecules inhibited adrenal neurosecretion activated via stimulation of native 3β4^* nAChR, with IC₅₀ values ranging from 0.4 to 13.0 µM. Using cells expressing recombinant 3β4 nAChRs, these molecules inhibited calcium accumulation (a more direct assay to establish nAChR activity), with IC₅₀ values ranging from 0.7 to 38.2 µM. Radiolabeled nAChR binding studies to orthosteric sites showed no inhibitory activity on either native or recombinant nAChRs. Correlation analyses of the data from both functional assays suggested additional, non-nAChR activity of the molecules. To test this hypothesis, the effects of the drugs on neurosecretion stimulated through non-nAChR mechanisms were investigated; inhibitory effects ranged from no inhibition to 95% inhibition at concentrations of 10 µM. Correlation analyses of the functional data confirmed this hypothesis. Several of the molecules (24/51) increased agonist binding to native nAChRs, supporting allosteric interactions with nAChRs. Computational modeling and blind docking identified a binding site for our negative allosteric modulators near the orthosteric binding site of the receptor. In summary, this study identified several molecules for potential development as negative allosteric modulators and documented the importance of multiple screening assays for nAChR drug discovery.

Address correspondence to: Dr. Dennis B. McKay, Division of Pharmacology, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH 43210. E-mail: mckay.2{at}osu.edu