Document Detail


NMDA antagonist activity of (+/-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl)piperidine-2-carboxylic acid resides with the (-)-2R,4S-isomer.
MedLine Citation:
PMID:  1387167     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The tetrazole-substituted amino acid (+/-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl)pip eri dine-2-carboxylic acid (LY233053, (+/-)-1) was resolved into its constituent enantiomers by treatment of a key intermediate in the synthesis of the racemic amino acid, ethyl (+/-)-cis-4-(cyanomethyl)-N-allylpiperidine-2-carboxylate, with either 2S,3S- or 2R,3R-di-p-toluoyltartaric acid. These resolved amines were then converted as for the racemate to the amino acids (-)-1 and (+)-1. The activity of this potent and selective NMDA antagonist was found to reside with the (-)-isomer of 1 (LY235723). X-ray crystallographic analysis of the 2S,3S-di-p-toluoyltartaric acid salt of ethyl cis-4-(cyanomethyl)-N-allylpiperidine-2-carboxylate showed that the resolved amine, and thus (-)-1, possessed the 2R,4S absolute stereochemistry. Affinity for the NMDA receptor was determined using the specific radioligand [3H]-(2SR,4RS)-4-(phosphonomethyl)piperidine-2-carboxylic acid ([3H]CGS 19755; IC50 = 67 +/- 6 nM), and selective NMDA antagonist activity was determined using a cortical slice preparation (IC50 versus 40 microM NMDA = 1.9 +/- 0.24 microM). This compound also demonstrated potent NMDA antagonist activity in vivo following systemic administration through its ability to block NMDA-induced convulsions in neonatal rats, NMDA-induced lethality in mice, and NMDA-induced striatal neuronal degeneration in rats.
Authors:
P L Ornstein; D D Schoepp; M B Arnold; N D Jones; J B Deeter; D Lodge; J D Leander
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  35     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1992 Aug 
Date Detail:
Created Date:  1992-09-22     Completed Date:  1992-09-22     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3111-5     Citation Subset:  IM    
Affiliation:
Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, Indiana 46285.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Corpus Striatum / drug effects
Mice
Molecular Structure
N-Methylaspartate / antagonists & inhibitors*,  pharmacology
Nerve Degeneration / drug effects
Pipecolic Acids / chemistry,  metabolism,  pharmacology*,  therapeutic use
Rats
Receptors, N-Methyl-D-Aspartate / drug effects,  metabolism
Seizures / chemically induced,  prevention & control
Stereoisomerism
Structure-Activity Relationship
Tetrazoles / chemistry,  pharmacology*,  therapeutic use
X-Ray Diffraction
Chemical
Reg. No./Substance:
0/Pipecolic Acids; 0/Receptors, N-Methyl-D-Aspartate; 0/Tetrazoles; 110347-85-8/selfotel; 125546-04-5/LY 233053; 6384-92-5/N-Methylaspartate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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