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NEUROPHARMACOLOGY

Old and New Pharmacology: Positive Allosteric Modulation of the 7 Nicotinic Acetylcholine Receptor by the 5-Hydroxytryptamine_2B/C Receptor Antagonist SB-206553 (3,5-Dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']di pyrrole-1(2H)-carboxamide)

Discovery Neuroscience (J.D., T.L., B.J., S.G., F.J., A.K., M.R.B., D.K., T.A.C.) and Chemical and Screening Sciences (A.G., J.L., V.S.), Wyeth Research, Princeton, New Jersey; Wyeth Applied Neurophysiology Group, University of Bristol, Bristol, United Kingdom (F.S., A.R., J.B.); and Siena Biotech S.p.A., Siena, Italy (R.R.)

The 7 nicotinic acetylcholine receptor (nAChR) has been implicated in Alzheimer's disease and schizophrenia, leading to efforts targeted toward discovering agonists and positive allosteric modulators (PAMs) of this receptor. In a Ca²⁺ flux fluorometric imaging plate reader assay, SB-206553 (3,5-dihydro-5-methyl -N-3-pyridinylbenzo [1, 2-b:4,5 -b']-di pyrrole-1(2H)-carboxamide), a compound known as a 5-hydroxytryptamine_2B/2C receptor antagonist, produced an 8-fold potentiation of the evoked calcium signal in the presence of an EC₂₀ concentration of nicotine and a corresponding EC₅₀ of 1.5 µM for potentiation of EC₂₀ nicotine responses in GH4C1 cells expressing the 7 receptor. SB-206553 was devoid of direct 7 receptor agonist activity and selective against other nicotinic receptors. Confirmation of the PAM activity of SB-206553 on the 7 nAChR was obtained in patch-clamp electrophysiological experiments in GH4C1 cells, where it failed to evoke any detectable currents when applied alone, yet dramatically potentiated the currents evoked by an EC₂₀ (17 µM) and EC₁₀₀ (124 µM) of acetylcholine (ACh). Native nicotinic receptors in CA1 stratum radiatum interneurons of rat hippocampal slices could also be activated by ACh (200 µM), an effect that was entirely blocked by the 7-selective antagonist methyllycaconitine (MLA). These ACh currents were potentiated by SB-206553, which increased the area of the current response significantly, resulting in a 40-fold enhancement at 100 µM. In behavioral experiments in rats, SB-206553 reversed an MK-801 (dizocilpine maleate)-induced deficit in the prepulse inhibition of acoustic startle response, an effect attenuated in the presence of MLA. This latter observation provides further evidence in support of the potential therapeutic utility of 7 nAChR PAMs in schizophrenia.

Address correspondence to: John Dunlop, Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543. E-mail, Dunlopj{at}wyeth.com

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