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

• Published in: The Journal of pharmacology and experimental therapeutics 2011-01, Vol.336 (1), p.242-253
• Main Authors: Wallace, Tanya L, Callahan, Patrick M, Tehim, Ashok, Bertrand, Daniel, Tombaugh, Geoffrey, Wang, Shaojie, Xie, Walter, Rowe, Wayne B, Ong, Voon, Graham, Elizabeth, Terry, Jr, Alvin V, Rodefer, Joshua S, Herbert, Brian, Murray, Michael, Porter, Richard, Santarelli, Luca, Lowe, David A
• Format: Article
• Language: English
• Subjects: alpha7 Nicotinic Acetylcholine Receptor; Animals; Binding, Competitive - drug effects; Binding, Competitive - physiology; Bridged Bicyclo Compounds - pharmacology; Cell Line, Tumor; Cognition - drug effects; Cognition - 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; Sensory Gating - physiology; Xenopus laevis
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.171892

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.