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Discovery of 3-substituted aminocyclopentanes as potent and orally bioavailable NR2B subtype-selective NMDA antagonists.
- Source :
-
ACS chemical neuroscience [ACS Chem Neurosci] 2011 Jul 20; Vol. 2 (7), pp. 352-62. Date of Electronic Publication: 2011 Apr 15. - Publication Year :
- 2011
-
Abstract
- A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.
- Subjects :
- Administration, Oral
Animals
Benzopyrans metabolism
Biological Availability
Catalepsy chemically induced
Catalepsy drug therapy
Dogs
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels antagonists & inhibitors
Ether-A-Go-Go Potassium Channels metabolism
Female
Half-Life
Indicators and Reagents
Isomerism
Ligation
Macaca mulatta
Male
Neuralgia drug therapy
Parkinson Disease drug therapy
Piperidines metabolism
Rats
Rats, Sprague-Dawley
Spinal Nerves pathology
Cyclopentanes chemical synthesis
Cyclopentanes pharmacology
Drug Discovery methods
Excitatory Amino Acid Antagonists chemical synthesis
Excitatory Amino Acid Antagonists pharmacology
Oxadiazoles chemical synthesis
Oxadiazoles pharmacology
Pyrimidines chemical synthesis
Pyrimidines pharmacology
Receptors, N-Methyl-D-Aspartate antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1948-7193
- Volume :
- 2
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- ACS chemical neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 22816022
- Full Text :
- https://doi.org/10.1021/cn200013d