852567-69-2Relevant academic research and scientific papers
Convergent synthesis and pharmacology of substituted tetrazolyl-2-amino-3- (3-hydroxy-5-methyl-4-isoxazolyl)propionic acid analogues
Vogensen, Stine B.,Clausen, Rasmus P.,Greenwood, Jeremy R.,Johansen, Tommy N.,Pickering, Darryl S.,Nielsen, Birgitte,Ebert, Bjarke,Krogsgaard-Larsen, Povl
, p. 3438 - 3442 (2005)
The synthesis and pharmacological characterization of 1- and 2-alkyltetrazolyl analogues of (AS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-5- tetrazolyl)-4-isoxazolyl]propionicacid(2-Me-Tet-AMPA), a highly potent and selective agonist at AMPA receptors, are presented. A shorter and more convergent synthetic route than previously described, employing a new method for introducing the amino acid moiety, was developed for these derivatives. The 2-substituted isomers were selective agonists, and their activity correlated inversely with the size of the substituent. Structural explanations of the structure-activity relationship are provided.
The Synthesis and Evaluation of Fluoro-, Trifluoromethyl-, and Iodomuscimols as GABA Agonists
Abdul Manan, Mohd Abdul Fatah,Cordes, David B.,Slawin, Alexandra M. Z.,Bühl, Michael,Liao, Vivian W. Y.,Chua, Han. C.,Chebib, Mary,O'Hagan, David
supporting information, p. 10848 - 10852 (2017/08/18)
Halogenated analogues of the neurotoxic alkaloid muscimol were prepared with fluorine, iodine or trifluoromethyl at the 4 position of the isoxazole ring system. These compounds were investigated as agonists for GABAA receptors. Only the C-4 fluorine-containing analogue proved to be an active compound in these assays. The fluoro analogue was less active than muscimol, however it showed differential activity between synaptic (α1β2γ2) and extrasynaptic (α4β2γ) GABAA receptors, having a similar potency to the neurotransmitter GABA for the extrasynaptic (α4β2γ) receptor.
O-Alkylation of 3-hydroxyisoxazoles predominates under Mitsunobu conditions
Chen, Lijia,Fletcher, Steven
, p. 1693 - 1696 (2014/03/21)
Regiochemical control in the functionalization of ambident nucleophiles is of particular interest in organic chemistry. Herein, we demonstrate that O-alkylation of ambident 3-hydroxyisoxazoles, which are heterocyclic bioisosteres of carboxylic acids, predominates under Mitsunobu conditions. In several cases, excellent O-regioselectivity (≥95%) was observed. It is noteworthy that reactions were complete within 15 min at room temperature. Furthermore, the conditions are compatible with a range of alcohols that cover all of the typical protecting groups for the 3-hydroxyisoxazole motif, providing milder, simpler and less hazardous protocols to those commonly followed in the literature.
Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as γ-aminobutyric acidA receptor agonists
Petersen, Jette G.,Bergmann, Rikke,M?ller, Henriette A.,J?rgensen, Charlotte G.,Nielsen, Birgitte,Kehler, Jan,Frydenvang, Karla,Kristensen, Jesper,Balle, Thomas,Jensen, Anders A.,Kristiansen, Uffe,Fr?lund, Bente
, p. 993 - 1006 (2013/03/28)
A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABAA receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABAA receptors. The unsubstituted 4-AHP analogue (2a) (EC 50 19 μM, Rmax 69%) was a moderately potent agonist at human α1β2γ2 GABAA receptors, and in SAR studies substitutions in the 3- and/or 5-position were found to be detrimental to binding affinities. Ligand-receptor docking in an α1β2γ2 GABAA receptor homology model along with the obtained SAR indicate that 2a and muscimol share a common binding mode, which deviates from the binding mode of the structurally related antagonist series based on 4-(piperidin-4-yl)-1- hydroxypyrazole (4-PHP, 1). Selectivity for α1β 2γ2 over ρ1 GABAA receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of 2a illustrating that even small differences in structure can give rise to subtype selectivity.
