title: Old and new pharmacology: positive allosteric modulation of the alpha7 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).
abstract: The alpha7 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 EC(20) concentration of nicotine and a corresponding EC(50) of 1.5 muM for potentiation of EC(20) nicotine responses in GH4C1 cells expressing the alpha7 receptor. SB-206553 was devoid of direct alpha7 receptor agonist activity and selective against other nicotinic receptors. Confirmation of the PAM activity of SB-206553 on the alpha7 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 microM) and EC(100) (124 microM) of acetylcholine (ACh). Native nicotinic receptors in CA1 stratum radiatum interneurons of rat hippocampal slices could also be activated by ACh (200 microM), an effect that was entirely blocked by the alpha7-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 microM. 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 alpha7 nAChR PAMs in schizophrenia.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA. Dunlopj@wyeth.com
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.forename: Tim
authors.initials: T
authors.lastname: Lock
authors.forename: Brian
authors.initials: B
authors.lastname: Jow
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Sitzia
authors.forename: Steven
authors.initials: S
authors.lastname: Grauer
authors.forename: Flora
authors.initials: F
authors.lastname: Jow
authors.forename: Angela
authors.initials: A
authors.lastname: Kramer
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bowlby
authors.forename: Andrew
authors.initials: A
authors.lastname: Randall
authors.forename: Dianne
authors.initials: D
authors.lastname: Kowal
authors.forename: Adam
authors.initials: A
authors.lastname: Gilbert
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: James
authors.initials: J
authors.lastname: Larocque
authors.forename: Veronica
authors.initials: V
authors.lastname: Soloveva
authors.forename: Jon
authors.initials: J
authors.lastname: Brown
authors.forename: Renza
authors.initials: R
authors.lastname: Roncarati
mesh_terms: D000818:Animals; D002460:Cell Line; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000196:embryology; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014162:Transfection; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D007211:Indoles; D011725:Pyridines; D011978:Receptors, Nicotinic; D044348:Receptors, Serotonin, 5-HT2; D012702:Serotonin Antagonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; C094868:SB 206553