| GABA agonists. Resolution, absolute stereochemistry, and enantioselectivity of (S)-(+)- and (R)-(-)-dihydromuscimol. | |
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MedLine Citation:
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PMID: 2999396 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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(RS)-5-(Aminomethyl)-2-isoxazolin-3-ol (dihydromuscimol, DHM) is a potent 4-aminobutyric acid (GABA) agonist, the inhibitory effects of which on neurons are sensitive to the antagonist bicuculline methochloride (BMC), and it also interacts with the GABA uptake system in vitro. (S)-(+)-DHM (4) and (R)-(-)-DHM (5) were obtained in optically pure forms via resolution of tert-butyloxycarbonyl-protected DHM (1) using cinchonidine as the only resolving agent. The optical purity and absolute stereochemistry of 4 and 5 were established by chemical correlation to the (S)-(+) enantiomer of 3-hydroxy-4-aminobutyric acid (GABOB). While 4 was a specific and potent BMC-sensitive GABA agonist in vivo and in vitro, possibly the most potent GABA agonist so far described, the inhibition of GABA uptake by DHM proved to reside exclusively in the (R)-(-) enantiomer (5). The affinity of 5 for BMC-sensitive GABA receptor sites in vitro was some 50 times lower than that of 4. Compounds 4 and 5 can be considered semirigid isosteres of the conformationally flexible GABA analogues (S)-(+)- and (R)-(-)-GABOB, respectively, which show a very low degree of enantioselectivity with respect to GABA synaptic mechanisms. This correlation between the degree of enantioselectivity and conformational mobility of chiral GABA analogues might be of importance for the design of new drugs with specific actions at synapses at which GABA is the transmitter. |
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Authors:
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P Krogsgaard-Larsen; L Nielsen; E Falch; D R Curtis |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 28 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1985 Nov |
Date Detail:
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Created Date: 1985-12-27 Completed Date: 1985-12-27 Revised Date: 2008-11-21 |
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: 1612-7 Citation Subset: IM |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bicuculline / analogs & derivatives, pharmacology Brain / drug effects, metabolism Cats Chemical Phenomena Chemistry Diazepam / metabolism Isoxazoles / metabolism Molecular Conformation Muscimol / analogs & derivatives*, isolation & purification, pharmacology Neurons / drug effects, physiology Oxazolidinones* Piperidines / metabolism Rats Receptors, GABA-A / drug effects, metabolism Spinal Cord / cytology Stereoisomerism Structure-Activity Relationship Synaptic Membranes / metabolism gamma-Aminobutyric Acid / analogs & derivatives, metabolism*, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Isoxazoles; 0/Oxazolidinones; 0/Piperidines; 0/Receptors, GABA-A; 2763-96-4/Muscimol; 352-21-6/4-amino-3-hydroxybutyric acid; 38641-83-7/bicuculline methochloride; 439-14-5/Diazepam; 485-49-4/Bicuculline; 56-12-2/gamma-Aminobutyric Acid; 64603-91-4/4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol; 72241-46-4/dihydromuscimol; 72450-62-5/piperidine-4-sulfonic acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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