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

The α7 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 α7 nicotinic acetylcholine receptor partial agonist, in relationship to α7 nicotinic acetylcholine receptor occupancy. BMS-902483 ha...

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Bibliographic Details
Published in:European journal of pharmacology 2017-07, Vol.807, p.1-11
Main Authors: Pieschl, Rick L., Miller, Regina, Jones, Kelli M., Post-Munson, Debra J., Chen, Ping, Newberry, Kimberly, Benitex, Yulia, Molski, Thaddeus, Morgan, Daniel, McDonald, Ivar M., Macor, John E., Olson, Richard E., Asaka, Yukiko, Digavalli, Siva, Easton, Amy, Herrington, James, Westphal, Ryan S., Lodge, Nicholas J., Zaczek, Robert, Bristow, Linda J., Li, Yu-Wen
Format: Article
Language:English
Subjects:
alpha7 Nicotinic Acetylcholine Receptor - agonists
Animals
Attention - drug effects
Behavior
Cognition - drug effects
Dose-Response Relationship, Drug
Drug Partial Agonism
Ex vivo
HEK293 Cells
Hippocampus - drug effects
Hippocampus - physiology
Humans
Long-Term Potentiation - drug effects
LTP
Male
Memory - drug effects
Mice
Nicotinic
Nicotinic Agonists - pharmacology
Partial agonist
Quinuclidines - pharmacology
Rats
Sensory Gating - drug effects
Spiro Compounds - pharmacology
Target engagement
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Summary:The α7 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 α7 nicotinic acetylcholine receptor partial agonist, in relationship to α7 nicotinic acetylcholine receptor occupancy. BMS-902483 has low nanomolar affinity for rat and human α7 nicotinic acetylcholine receptors and elicits currents in cells expressing human or rat α7 nicotinic acetylcholine receptors that are about 60% of the maximal acetylcholine response. BMS-902483 improved 24h novel object recognition memory in mice with a minimal effective dose (MED) of 0.1mg/kg and reversed MK-801-induced deficits in a rat attentional set-shifting model of executive function with an MED of 3mg/kg. Enhancement of novel object recognition was blocked by the silent α7 nicotinic acetylcholine receptor agonist, NS6740, demonstrating that activity of BMS-902483 was mediated by α7 nicotinic acetylcholine receptors. BMS-902483 also reversed ketamine-induced deficits in auditory gating in rats, and enhanced ex vivo hippocampal long-term potentiation examined 24h after dosing in mice. Results from an ex vivo brain homogenate binding assay showed that α7 receptor occupancy ranged from 64% (novel object recognition) to ~90% (set shift and gating) at the MED for behavioral and sensory processing effects of BMS-902483.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2017.04.024