| NMDA antagonist activity of (+/-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl)piperidine-2-carboxylic acid resides with the (-)-2R,4S-isomer. | |
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MedLine Citation:
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PMID: 1387167 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 35 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1992 Aug |
Date Detail:
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Created Date: 1992-09-22 Completed Date: 1992-09-22 Revised Date: 2004-11-17 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 3111-5 Citation Subset: IM |
Affiliation:
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Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, Indiana 46285. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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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