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.
Keywords:
NMDA; NR2B antagonist; Parkinson’s disease; neuropathic pain.
MeSH terms
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Administration, Oral
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Animals
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Benzopyrans / metabolism
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Biological Availability
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Catalepsy / chemically induced
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Catalepsy / drug therapy
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / pharmacology*
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Dogs
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Drug Discovery / methods*
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Ether-A-Go-Go Potassium Channels / metabolism
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Excitatory Amino Acid Antagonists / chemical synthesis*
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Excitatory Amino Acid Antagonists / pharmacology*
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Female
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Half-Life
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Indicators and Reagents
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Isomerism
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Ligation
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Macaca mulatta
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Male
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Neuralgia / drug therapy
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Oxadiazoles / chemical synthesis*
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Oxadiazoles / pharmacology*
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Parkinson Disease / drug therapy
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Piperidines / metabolism
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
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Spinal Nerves / pathology
Substances
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Benzopyrans
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Cyclopentanes
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Excitatory Amino Acid Antagonists
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Indicators and Reagents
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N-(3-(3-(4-methylbenzyl)-1,2,4-oxadiazol-5-yl)cyclopentyl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine
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NR2B NMDA receptor
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Oxadiazoles
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Piperidines
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Pyrimidines
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Receptors, N-Methyl-D-Aspartate
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L 706000