Document Detail

RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents.
MedLine Citation:
PMID:  20959364     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-19
Journal Detail:
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:
Created Date:  2010-12-16     Completed Date:  2011-01-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  242-53     Citation Subset:  IM    
CNS Discovery Research, Roche Palo Alto LLC, Palo Alto, California, USA.
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MeSH Terms
Bicyclo Compounds / pharmacology*
Binding, Competitive / drug effects,  physiology
Cell Line, Tumor
Cognition / drug effects,  physiology*
Drug Partial Agonism*
Indazoles / pharmacology*
Nicotinic Agonists / pharmacology*
Rats, Inbred F344
Rats, Long-Evans
Rats, Sprague-Dawley
Rats, Wistar
Receptors, Nicotinic / physiology*
Sensory Gating / drug effects,  physiology*
Xenopus laevis
Reg. No./Substance:
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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