The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia

Autor: Debra J. Post-Munson, Ping Chen, Linda J. Bristow, Daniel G. Morgan, Ryan Westphal, Kelli M. Jones, Adam Hendricson, Lizbeth Gallagher, Dalton King, Yulia Benitex, Richard Pieschl, Digavalli V. Sivarao, Christiana I. Iwuagwu, Robert Zaczek, Regina Lidge, Nicholas J. Lodge, John E. Macor, Amy Easton, James H. Cook, Yu-Wen Li, Thaddeus F. Molski, Richard E. Olson, Christopher Daly
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
Nicotinic Acetylcholine Receptors
Quinuclidines
Patch-Clamp Techniques
alpha7 Nicotinic Acetylcholine Receptor
Drug Evaluation
Preclinical
lcsh:Medicine
Pharmacology
Biochemistry
Mice
Radioligand Assay
0302 clinical medicine
Cognition
Mathematical and Statistical Techniques
Medicine and Health Sciences
lcsh:Science
Receptor
Animal Management
Cognitive Impairment
Multidisciplinary
Chemistry
Pharmaceutics
Cognitive Neurology
Agriculture
Nicotinic acetylcholine receptor
Nicotinic agonist
Neurology
Physical Sciences
Acetylcholine
Statistics (Mathematics)
medicine.drug
Research Article
Signal Transduction
Agonist
Transmembrane Receptors
medicine.drug_class
Cognitive Neuroscience
Research and Analysis Methods
Partial agonist
03 medical and health sciences
Drug Therapy
Mental Health and Psychiatry
medicine
Animals
Humans
Spiro Compounds
Statistical Methods
Phencyclidine
Acetylcholine receptor
Animal Performance
Analysis of Variance
lcsh:R
Biology and Life Sciences
Proteins
Cell Biology
Rats
030104 developmental biology
HEK293 Cells
Acetylcholine Receptors
Schizophrenia
Cognitive Science
lcsh:Q
Cognition Disorders
030217 neurology & neurosurgery
Mathematics
Neuroscience
Serotonin Receptors
Zdroj: PLoS ONE
PLoS ONE, Vol 11, Iss 7, p e0159996 (2016)
ISSN: 1932-6203
Popis: The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc) and set shift performance in rats (1-10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po). BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc) and mismatch negativity (0.03-3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.
Databáze: OpenAIRE
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