RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents

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

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

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 (Ki = 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 [IC50 = 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.

Original languageEnglish (US)
Pages (from-to)243-253
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume336
Issue number1
DOIs
StatePublished - Jan 1 2011

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Sensory Gating
Nicotinic Receptors
Cognition
Rodentia
Oocytes
Receptors, Serotonin, 5-HT3
Phencyclidine
Episodic Memory
N-((3S)-1-azabicyclo(2.2.2)oct-3-yl)-1H-indazole-3-carboxamide hydrochloride
Apomorphine
Central Nervous System Diseases
Executive Function
Brain
Short-Term Memory
Inhibitory Concentration 50
Acetylcholine
Cell Line
Water

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents. / Wallace, Tanya L.; Callahan, Patrick M.; Tehim, Ashok; Bertrand, Daniel; Tombaugh, Geoffrey; Wang, Shaojie; Xie, Walter; Rowe, Wayne B.; Ong, Voon; Graham, Elizabeth; Terry, Alvin V.; Rodefer, Joshua S.; Herbert, Brian; Murray, Michael; Porter, Richard; Santarelli, Luca; Lowe, David A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 336, No. 1, 01.01.2011, p. 243-253.

Research output: Contribution to journalArticle

Wallace, TL, Callahan, PM, Tehim, A, Bertrand, D, Tombaugh, G, Wang, S, Xie, W, Rowe, WB, Ong, V, Graham, E, Terry, AV, Rodefer, JS, Herbert, B, Murray, M, Porter, R, Santarelli, L & Lowe, DA 2011, 'RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents', Journal of Pharmacology and Experimental Therapeutics, vol. 336, no. 1, pp. 243-253. https://doi.org/10.1124/jpet.110.171892
Wallace, Tanya L. ; Callahan, Patrick M. ; Tehim, Ashok ; Bertrand, Daniel ; Tombaugh, Geoffrey ; Wang, Shaojie ; Xie, Walter ; Rowe, Wayne B. ; Ong, Voon ; Graham, Elizabeth ; Terry, Alvin V. ; Rodefer, Joshua S. ; Herbert, Brian ; Murray, Michael ; Porter, Richard ; Santarelli, Luca ; Lowe, David A. / RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents. In: Journal of Pharmacology and Experimental Therapeutics. 2011 ; Vol. 336, No. 1. pp. 243-253.
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