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

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Tytuł:: Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents.
Autorzy:: Pieschl RL; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Miller R; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Jones KM; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Post-Munson DJ; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Chen P; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Newberry K; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Benitex Y; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Molski T; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Morgan D; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
McDonald IM; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Macor JE; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Olson RE; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Asaka Y; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Digavalli S; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Easton A; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Herrington J; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Westphal RS; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Lodge NJ; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Zaczek R; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Bristow LJ; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Li YW; Bristol-Myers Squibb Company, Department of Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: .
Źródło:: European journal of pharmacology [Eur J Pharmacol] 2017 Jul 15; Vol. 807, pp. 1-11. Date of Electronic Publication: 2017 Apr 22.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Publication: 2005- : Amsterdam : Elsevier Science
Original Publication: Amsterdam, North Holland Pub. Co.
MeSH Terms:: Drug Partial Agonism*
Cognition/*drug effects
Nicotinic Agonists/*pharmacology
Quinuclidines/*pharmacology
Sensory Gating/*drug effects
Spiro Compounds/*pharmacology
alpha7 Nicotinic Acetylcholine Receptor/*agonists
Animals ; Attention/drug effects ; Dose-Response Relationship, Drug ; HEK293 Cells ; Hippocampus/drug effects ; Hippocampus/physiology ; Humans ; Long-Term Potentiation/drug effects ; Male ; Memory/drug effects ; Mice ; Rats
Contributed Indexing:: Keywords: Behavior; Ex vivo; LTP; Nicotinic; Partial agonist; Target engagement
Substance Nomenclature:: 0 (BMS-902483)
0 (Nicotinic Agonists)
0 (Quinuclidines)
0 (Spiro Compounds)
0 (alpha7 Nicotinic Acetylcholine Receptor)
Entry Date(s):: Date Created: 20170426 Date Completed: 20171205 Latest Revision: 20171205
Update Code:: 20240105
DOI:: 10.1016/j.ejphar.2017.04.024
PMID:: 28438647
: Czasopismo naukowe

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.
(Copyright © 2017 Elsevier B.V. All rights reserved.)

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