Linked Life Data

1825117

Source:http://linkedlifedata.com/resource/pubmed/id/1825117

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1991-3-12
pubmed:abstractText
We have prepared a series of cis-4-(tetrazolylakyl)piperidine-2-carboxylic acids as potent and selective N-methyl-D-aspartic acid (NMDA) receptor antagonists. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated in vitro in both receptor binding assays [( 3H]CGS-19755, [3H]AMPA, and [3H]kainic acid) and in a cortical-wedge preparation (versus NMDA, quisqualic acid, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced convulsions in neonatal rats and NMDA-induced lethality in mice. The most potent compound of this series, 15 (LY233053), selectively displaced [3H]CGS-19755 binding with an IC50 of 107 +/- 7 nM and selectively antagonized responses due to NMDA in a cortical-wedge preparation with an IC50 of 4.2 +/- 0.4 microM. Compound 15 blocked both NMDA-induced convulsions in neonatal rats (minimum effective dose (MED) = 20 mg/kg ip) and NMDA-induced lethality in mice (MED = 5 mg/kg ip). This is the first example of an NMDA receptor antagonist that incorporates a tetrazole moiety as an omega-acid bioisostere. These amino acid antagonists are also unique from their phosphonic acid counterparts in that they have a shorter duration of action in vivo. For the treatment of acute disorders such as stroke, where an NMDA antagonist would be administered parenterally, the shorter duration of action may be beneficial, e.g., allowing for better dosage control. The combination of potent NMDA receptor antagonism and a short duration of action may make these compounds useful therapeutic agents in the treatment of a variety of neurological disorders.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
34
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
90-7
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1991
pubmed:articleTitle
4-(Tetrazolylalkyl)piperidine-2-carboxylic acids. Potent and selective N-methyl-D-aspartic acid receptor antagonists with a short duration of action.
pubmed:affiliation
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
pubmed:publicationType
Journal Article, Comparative Study