| RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents. | |
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MedLine Citation:
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PMID: 20959364 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Neuronal nicotinic α7 acetylcholine receptors (α7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at α7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) binds potently to the human α7nAChR (K(i) = 6 nM), in which it acts as a partial agonist (63-69% of acetylcholine) as assessed by whole-cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human α7nAChRs with an EC(50) of 0.8 μM (oocytes) and 7.7 μM (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC(50) = 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: ≤0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent α7nAChR partial agonist that improves cognitive performance and sensorimotor gating. |
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Authors:
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Tanya L Wallace; Patrick M Callahan; Ashok Tehim; Daniel Bertrand; Geoffrey Tombaugh; Shaojie Wang; Walter Xie; Wayne B Rowe; Voon Ong; Elizabeth Graham; Alvin V Terry; Joshua S Rodefer; Brian Herbert; Michael Murray; Richard Porter; Luca Santarelli; David A Lowe |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-19 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 336 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-16 Completed Date: 2011-01-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 242-53 Citation Subset: IM |
Affiliation:
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CNS Discovery Research, Roche Palo Alto LLC, Palo Alto, California, USA. tanya.wallace@sri.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bicyclo Compounds / pharmacology* Binding, Competitive / drug effects, physiology Cell Line, Tumor Cognition / drug effects, physiology* Drug Partial Agonism* Female Humans Indazoles / pharmacology* Male Nicotinic Agonists / pharmacology* Rats Rats, Inbred F344 Rats, Long-Evans Rats, Sprague-Dawley Rats, Wistar Receptors, Nicotinic / physiology* Sensory Gating / drug effects, physiology* Xenopus laevis |
| Chemical | |
Reg. No./Substance:
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0/Bicyclo Compounds; 0/Indazoles; 0/N-((3S)-1-azabicyclo(2.2.2)oct-3-yl)-1H-indazole-3-carboxamide hydrochloride; 0/Nicotinic Agonists; 0/Receptors, Nicotinic; 0/alpha7 nicotinic acetylcholine receptor |
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