Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Med Chem
2013 Nov 14;5621:8352-65. doi: 10.1021/jm400704g.
Show Gene links
Show Anatomy links
Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of α7 nicotinic acetylcholine receptors.
Hogenkamp DJ
,
Ford-Hutchinson TA
,
Li WY
,
Whittemore ER
,
Yoshimura RF
,
Tran MB
,
Johnstone TB
,
Bascom GD
,
Rollins H
,
Lu L
,
Gee KW
.
???displayArticle.abstract???
A series of novel arylpyrid-3-ylmethanones (7a-aa) were designed as modulators of α7 nicotinic acetylcholine receptors (nAChRs). The methanones were found to be type I positive allosteric modulators (PAMs) of human α7 nAChRs expressed in Xenopus ooctyes. Structure-activity relationship (SAR) studies resulted in the identification of compound 7v as a potent and efficacious type I PAM with maximum modulation of a nicotine EC5 response of 1200% and EC50 = 0.18 μM. Compound 7z was active in reversing the effect of scopolamine in the novel object recognition (NOR) paradigm with a minimum effective ip dose of 1.0 mg/kg (2.7 μmol/kg). This effect was blocked by the selective α7 nAChR antagonist methyllycaconitine (MLA). These compounds are potent type I positive allosteric modulators of α7 nAChRs that may have therapeutic value in restoring impaired sensory gating and cognitive deficits in schizophrenia and Alzheimer's disease.
???displayArticle.pubmedLink???
24098954
???displayArticle.pmcLink???PMC3912855 ???displayArticle.link???J Med Chem ???displayArticle.grants???[+]
Briggs,
Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors.
2009, Pubmed,
Xenbase
Briggs,
Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors.
2009,
Pubmed
,
Xenbase
Dinklo,
Characterization of 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a novel positive allosteric modulator of the {alpha}7 nicotinic acetylcholine receptor.
2011,
Pubmed
Dunlop,
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).
2009,
Pubmed
Ennaceur,
A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data.
1988,
Pubmed
Faghih,
Allosteric modulators of the alpha7 nicotinic acetylcholine receptor.
2008,
Pubmed
Freedman,
Initial phase 2 trial of a nicotinic agonist in schizophrenia.
2008,
Pubmed
Gee,
Limiting activity at beta1-subunit-containing GABAA receptor subtypes reduces ataxia.
2010,
Pubmed
,
Xenbase
Gee,
Modulation of the chloride ionophore by benzodiazepine receptor ligands: influence of gamma-aminobutyric acid and ligand efficacy.
1986,
Pubmed
Gotti,
Structural and functional diversity of native brain neuronal nicotinic receptors.
2009,
Pubmed
Gotti,
Brain neuronal nicotinic receptors as new targets for drug discovery.
2006,
Pubmed
Grønlien,
Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes.
2007,
Pubmed
,
Xenbase
Hajós,
Targeting alpha7 nicotinic acetylcholine receptors in the treatment of schizophrenia.
2010,
Pubmed
Hawkinson,
3 alpha-Hydroxy-3 beta-trifluoromethyl-5 alpha-pregnan-20-one (Co 2-1970): a partial agonist at the neuroactive steroid site of the gamma-aminobutyric acidA receptor.
1996,
Pubmed
,
Xenbase
Haydar,
Neuronal nicotinic acetylcholine receptors - targets for the development of drugs to treat cognitive impairment associated with schizophrenia and Alzheimer's disease.
2010,
Pubmed
Hogenkamp,
Enaminone amides as novel orally active GABAA receptor modulators.
2007,
Pubmed
Hogg,
Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors.
2007,
Pubmed
Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase
Jensen,
Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations.
2005,
Pubmed
Johnstone,
Allosteric modulation of related ligand-gated ion channels synergistically induces long-term potentiation in the hippocampus and enhances cognition.
2011,
Pubmed
,
Xenbase
Koike,
Tropisetron improves deficits in auditory P50 suppression in schizophrenia.
2005,
Pubmed
Kuhn,
Intramolecular hydrogen bonding in medicinal chemistry.
2010,
Pubmed
Leiser,
A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits.
2009,
Pubmed
Lieberman,
A randomized exploratory trial of an α-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia.
2013,
Pubmed
Malysz,
Evaluation of alpha7 nicotinic acetylcholine receptor agonists and positive allosteric modulators using the parallel oocyte electrophysiology test station.
2009,
Pubmed
,
Xenbase
Ng,
Nootropic alpha7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators.
2007,
Pubmed
,
Xenbase
Olincy,
Nicotinic mechanisms in the treatment of psychotic disorders: a focus on the α7 nicotinic receptor.
2012,
Pubmed
Razgulin,
Binding properties of aromatic carbon-bound fluorine.
2006,
Pubmed
Santilli,
2-Oxo-1,8-naphthyridine-3-carboxylic acid derivatives with potent gastric antisecretory properties.
1987,
Pubmed
Sitzia,
Voltage- and Temperature-Dependent Allosteric Modulation of α7 Nicotinic Receptors by PNU120596.
2011,
Pubmed
Taly,
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.
2009,
Pubmed
Topliss,
A manual method for applying the Hansch approach to drug design.
1977,
Pubmed
Wallace,
Targeting the nicotinic alpha7 acetylcholine receptor to enhance cognition in disease.
2011,
Pubmed
Williams,
Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations.
2011,
Pubmed
Williams,
Intrinsically low open probability of α7 nicotinic acetylcholine receptors can be overcome by positive allosteric modulation and serum factors leading to the generation of excitotoxic currents at physiological temperatures.
2012,
Pubmed
,
Xenbase
