Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents

The alpha 7 nicotinic acetylcholine receptor is thought to play an important role in human cognition. Here we describe the in vivo effects of BMS-902483, a selective potent alpha 7 nicotinic acetylcholine receptor partial agonist, in relationship to alpha 7 nicotinic acetylcholine receptor occupancy. BMS-902483 has low nanomolar affinity for rat and human alpha 7 nicotinic acetylcholine receptors and elicits currents in cells expressing human or rat alpha 7 nicotinic acetylcholine receptors that are about 60% of the maximal acetylcholine response. BMS-902483 improved 24 h novel object recognition memory in mice with a minimal effective dose (MED) of 0.1 mg/kg and reversed MK-801-induced deficits in a rat attentional set-shifting model of executive function with an MED of 3 mg/kg. Enhancement of novel object recognition was blocked by the silent alpha 7 nicotinic acetylcholine receptor agonist, NS6740, demonstrating that activity of BMS-902483 was mediated by alpha 7 nicotinic acetylcholine receptors. BMS-902483 also reversed ketamine-induced deficits in auditory gating in rats, and enhanced ex vivo hippocampal long-term potentiation examined 24 h after dosing in mice. Results from an ex vivo brain homogenate binding assay showed that alpha 7 receptor occupancy ranged from 64% (novel object recognition) to similar to 90% (set shift and gating) at the MED for behavioral and sensory processing effects of BMS-902483.