| Orally active and potent inhibitors of gamma-aminobutyric acid uptake. | |
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MedLine Citation:
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PMID: 2985785 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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3-Pyrrolidineacetic acid (1a), certain piperidinecarboxylic acids--i.e., 3-piperidinecarboxylic acid (2a), 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (3a), and cis-4-hydroxy-3-piperidinecarboxylic acid (4a)--cis-3-aminocyclohexanecarboxylic acid (5a, cis-3-ACHC), and gamma-aminobutyric acid (6a, GABA) itself are among the most potent inhibitors of [3H]GABA uptake by neurons and glia in vitro. These hydrophilic amino acids, however, do not readily enter the central nervous system in pharmacologically significant amounts following peripheral administration. We now report that N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (2b) is a specific GABA-uptake inhibitor that is more potent, more lipophilic and, in limited testing, as selective as 2a. Similar results were obtained with the N-(4,4-diphenyl-3-butenyl) derivatives of 1a, 3a, and 4a. By contrast, N-(4,4-diphenyl-3-butenyl) derivatives of 5a and 6a were not more potent than the parent amino acids and appear to inhibit GABA uptake, at least in part, by a nonselective mechanism of action. The N-(4,4-diphenyl-3-butenyl)amino acids 1b-4b exhibit anticonvulsant activity in rodents following oral or intraperitoneal administration [Yunger, L.M.; et al. J. Pharmacol. Exp. Ther. 1984, 228, 109]. |
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Authors:
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F E Ali; W E Bondinell; P A Dandridge; J S Frazee; E Garvey; G R Girard; C Kaiser; T W Ku; J J Lafferty; G I Moonsammy |
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Publication Detail:
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Type: In Vitro; Journal Article |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 28 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1985 May |
Date Detail:
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Created Date: 1985-06-03 Completed Date: 1985-06-03 Revised Date: 2006-11-15 |
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: 653-60 Citation Subset: IM |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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4-Aminobutyrate Transaminase
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metabolism Administration, Oral Alkylation Amino Acids / chemical synthesis*, pharmacology Animals Brain / metabolism Carboxylic Acids / chemical synthesis*, pharmacology Glutamate Decarboxylase / metabolism Male Neurotransmitter Uptake Inhibitors / administration & dosage, chemical synthesis* Norepinephrine / metabolism Rats Rats, Inbred Strains Receptors, GABA-A / metabolism Receptors, Neurotransmitter / metabolism Stereoisomerism Synaptosomes / metabolism gamma-Aminobutyric Acid / metabolism, physiology* |
| Chemical | |
Reg. No./Substance:
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0/Amino Acids; 0/Carboxylic Acids; 0/Neurotransmitter Uptake Inhibitors; 0/Receptors, GABA-A; 0/Receptors, Neurotransmitter; 51-41-2/Norepinephrine; 56-12-2/gamma-Aminobutyric Acid; EC 2.6.1.19/4-Aminobutyrate Transaminase; EC 4.1.1.15/Glutamate Decarboxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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