Old and New Pharmacology: Positive Allosteric Modulation of the α7 Nicotinic Acetylcholine Receptor by the 5-Hydroxytryptamine2B/C Receptor Antagonist SB-206553 (3,5-Dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b′]di pyrrole-1(2H)-carboxamide)

• Published in: The Journal of pharmacology and experimental therapeutics 2009-03, Vol.328 (3), p.766
• Main Authors: John Dunlop, Tim Lock, Brian Jow, Fabrizio Sitzia, Steven Grauer, Flora Jow, Angela Kramer, Mark R. Bowlby, Andrew Randall, Dianne Kowal, Adam Gilbert, Thomas A. Comery, James LaRocque, Veronica Soloveva, Jon Brown, Renza Roncarati
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.108.146514

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 Ca 2+ 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(2 H )-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 EC 20 concentration of nicotine and a corresponding EC 50 of 1.5 μM for potentiation of EC 20 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 EC 20 (17 μM) and EC 100 (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.