PT - JOURNAL ARTICLE AU - John Dunlop AU - Tim Lock AU - Brian Jow AU - Fabrizio Sitzia AU - Steven Grauer AU - Flora Jow AU - Angela Kramer AU - Mark R. Bowlby AU - Andrew Randall AU - Dianne Kowal AU - Adam Gilbert AU - Thomas A. Comery AU - James LaRocque AU - Veronica Soloveva AU - Jon Brown AU - Renza Roncarati TI - Old and New Pharmacology: Positive Allosteric Modulation of the α7 Nicotinic Acetylcholine Receptor by the 5-Hydroxytryptamine<sub>2B/C</sub> Receptor Antagonist SB-206553 (3,5-Dihydro-5-methyl-<em>N</em>-3-pyridinylbenzo[1,2-<em>b</em>:4,5-<em>b</em>′]di pyrrole-1(2<em>H</em>)-carboxamide) AID - 10.1124/jpet.108.146514 DP - 2009 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 766--776 VI - 328 IP - 3 4099 - http://jpet.aspetjournals.org/content/328/3/766.short 4100 - http://jpet.aspetjournals.org/content/328/3/766.full SO - J Pharmacol Exp Ther2009 Mar 01; 328 AB - The α7 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-hydroxytryptamine2B/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 α7 receptor. SB-206553 was devoid of direct α7 receptor agonist activity and selective against other nicotinic receptors. Confirmation of the PAM activity of SB-206553 on the α7 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 α7-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 α7 nAChR PAMs in schizophrenia. The American Society for Pharmacology and Experimental Therapeutics