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  • 1
    Electronic Resource
    Electronic Resource
    Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[4,5-c]pyridin-3-ol (1995)
    s.l. : American Chemical Society
    Journal of medicinal chemistry 38 (1995), S. 3287-3296 
    Details
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/jm00017a014
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  • 2
    Electronic Resource
    Electronic Resource
    GABAA agonists: Resolution and pharmacology of (+)- and (-)-isoguvacine oxide (1995)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 7 (1995), S. 434-438 
    Details
    ISSN: 0899-0042
    Keywords: chiral HPLC ; resolution ; enantiomeric purity ; GABAA receptor affinity ; GABAA agonist ; benzodiazepine stimulation ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: (3SR,4RS)-3,4-Epoxypiperidine-4-carboxylic acid (isoguvacine oxide) is a potent and specific GABAA receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAA receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)-1-(benzyloxycarbonyl)-3,4-epoxypiperidine-4-carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee ≥ 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABAB receptor sites (IC50 〉 100 μM), (+)-isoguvacine oxide (IC50 = 0.20 ± 0.03 μM) and (-)-isoguvacine oxide (IC50 = 0.32 ± 0.05 μM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAA receptor sites. Furthermore, (+)-isoguvacine oxide (EC50 = 6 μM; 33% relative efficacy) and (-)-isoguvacine oxide (EC50 = 5 μM; 38% efficacy relative to 10 μM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAA receptor-associated benzodiazepine site. This latter effect is an in vitro estimate of GABAA agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAA recognition site(s), derived from extensive structure - activity studies on GABAA agonists. Thus, the model of the GABAA recognition site(s) comprising a narrow cleft or pocket, in which the anionic moiety of the zwitterionic GABAA agonists is assumed to be embedded during receptor activation, may have to be revised. © 1995 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530070608
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  • 3
    Electronic Resource
    Electronic Resource
    GABAB antagonists: Enantiopharmacology of 5-amino-4-hydroxy-2-methylvaleric acid and X-ray structure of the eutomer (1995)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 7 (1995), S. 526-533 
    Details
    ISSN: 0899-0042
    Keywords: 5-aminovaleric acid (DAVA) ; 4-OH-DAVA ; 2-Me-4-OH-DAVA ; stereoisomers ; pharmacology ; GABAB antagonist ; GABAB receptor affinity ; X-ray analysis ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: We have previously shown that (R)-5-amino-4-hydroxyvaleric acid [(R)-4-OH-DAVA] and (S)-2-OH-DAVA bind to GABAB receptor sites and antagonize GABAB receptor-mediated function in a stereoselective manner. Furthermore, we have identified energy-minimized superimposable conformations of (R)-4-OH- and (S)-2-OH-DAVA which are assumed to reflect the receptor-active conformations of these compounds. This paper describes the in vitro enantiopharmacology of 5-amino-4-hydroxy-2-methylvaleric acid (2-Me-4-OH-DAVA). Whereas none of the four stereoisomers showed significant affinity for GABAA receptor sites or GABA uptake mechanisms in rat brain synaptic membranes, (2R,4R)-2-Me-4-OH-DAVA was shown to inhibit stereoselectively the binding of [3H]GABA to rat brain GABAB receptor sites (IC50 = 14 ± 4 μM). (2R,4R)-2-Me-4-OH-DAVA (Ki = 36 μM) and, with much lower potency, (2S,4R)-2-Me-4-OH-DAVA (Ki = 370 μM) stereoselectively antagonized GABAB receptor-mediated function in the isolated guinea pig ileum. The structure of the eutomer, (2R,4R)-2-Me-4-OH-DAVA, was established by an X-ray crystallographic analysis, and the solid-state conformation of (2R,4R)-2-Me-4-OH-DAVA was compared with the proposed receptor-active conformations of (R)-4-OH-DAVA and (S)-2-OH-DAVA. © 1995 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530070706
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    Paper (German National Licenses)
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