Abstract
Neuronal nicotinic alpha 7 acetylcholine receptors (α7nAChR) 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 CNS diseases (e.g., Alzheimer's). RG3487, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (C15H19ClN4O), 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, respectively. RG3487 activates human α7nAChRs with an EC50 = 0.8 μM (oocytes) and 7.7 μM (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor (5-HT3R; IC50 = 2.8 nM [oocytes], 32.7 nM [N1E-115 cells]). In vivo, RG3487 improved object recognition memory in rats following acute (minimally effective dose [MED]: 1.0 mg/kg, po) or repeated (10 day) administration at brain and plasma concentrations in the low nM range. Spatial learning deficits in age-impaired rats were reversed following RG3487 administration (MED: 0.03 mg/kg, ip) as evaluated in the Morris water-maze task. Using the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg, ip), and reversed PCP-induced impairments in an attentional set shifting model of executive function (MED: ≤0.03 mg/kg, ip). Cumulative evidence from these studies indicates RG3487 is a novel and potent α7nAChR partial agonist that improves cognitive performance and sensorimotor gating.
- Received July 15, 2010.
- Revision received October 16, 2010.
- Accepted October 18, 2010.
- The American Society for Pharmacology and Experimental Therapeutics