Document Detail

Pharmacological profile of NPC 17742 [2R,4R,5S-(2-amino-4,5-(1, 2-cyclohexyl)-7-phosphonoheptanoic acid)], a potent, selective and competitive N-methyl-D-aspartate receptor antagonist.
MedLine Citation:
PMID:  8423528     Owner:  NLM     Status:  MEDLINE    
2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid) (NPC 17742), the most potent isomer of the mixture 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626), was evaluated for activity in tests associated with receptors for excitatory amino acids. In receptor binding assays, NPC 17742 was selective for the N-methyl-D-aspartate (NMDA) receptor with a potency comparable to that of D(-, -3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid. Like (+/-)cis-4-phosphono-methyl-2-piperidine carboxylic acid (CGS 19755) and (+/-)(E)-2-amino-4-methyl-5-phosphono-3-penteneoic acid (CGP 37849), NPC 17742 competitively inhibited NMDA-induced enhancement of 1-[(2-thienyl)cyclohexyl]piperidine binding to the NMDA receptor ionophore and partially inhibited [3H]glycine binding to strychnine-insensitive sites. In contrast, NPC 17742 and CGP 37849 inhibited Mg(++)-stimulated 1-[(2-thienyl)cyclohexyl]piperidine binding in a noncompetitive fashion. In voltage-clamped Xenopus oocytes expressing excitatory amino acid receptors, NPC 17742 (pKB = 6.91) was equipotent with CGP 37849 (pKB = 7.17) in inhibiting NMDA-induced inward currents. Likewise, NPC 17742 (ED50 = 2.68 mg/kg) was equipotent with CGP 37849 and CGS 19755 in blocking NMDA-induced convulsions, but was less potent than these two compounds in the maximal electroshock test. Unlike CGP 37849 or CGS 19755, NPC 17742 potently antagonized seizures induced by pentylenetetrazol. In a model of global ischemia, low doses of NPC 17742 given either before or after ischemic result were effective in blocking damage to hippocampal CA1 neurons. The pharmacologic responses to NPC 17742 occurred at doses 30- to 300-fold lower than the acute lethal dose.(ABSTRACT TRUNCATED AT 250 WORDS)
J W Ferkany; G S Hamilton; R J Patch; Z Huang; S A Borosky; D L Bednar; B E Jones; R Zubrowski; J Willetts; E W Karbon
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  264     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1993 Jan 
Date Detail:
Created Date:  1993-02-23     Completed Date:  1993-02-23     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  256-64     Citation Subset:  IM    
Nova Pharmaceutical Corporation, Baltimore, Maryland.
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MeSH Terms
Amino Acids / metabolism,  pharmacology*,  toxicity
Anticonvulsants / pharmacology
Behavior, Animal / drug effects
Binding, Competitive
Brain Ischemia / drug therapy
Hippocampus / blood supply
Mice, Inbred Strains
N-Methylaspartate / pharmacology
Oocytes / drug effects,  physiology
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*,  metabolism
Xenopus laevis
Reg. No./Substance:
0/Amino Acids; 0/Anticonvulsants; 0/Receptors, N-Methyl-D-Aspartate; 117571-54-7/NPC 12626; 6384-92-5/N-Methylaspartate

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