AMPA Receptor Agonists:  Synthesis, Protolytic Properties, and Pharmacology of 3-Isothiazolol Bioisosteres of Glutamic Acid

A number of 3-isothiazolol bioisosteres of glutamic acid (1) and analogs of the AMPA receptor agonist, (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 2a), including (RS)-2-amino-3-(3-hydroxy-5-methylisothiazol-4-yl)propionic acid (thio-AMPA, 2b), were synthesized. Comparative...

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Veröffentlicht in:Journal of medicinal chemistry 1997-02, Vol.40 (4), p.520-527
Hauptverfasser: Matzen, Lisa, Engesgaard, Anne, Ebert, Bjarke, Didriksen, Michael, Frølund, Bente, Krogsgaard-Larsen, Povl, Jaroszewski, Jerzy W
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Sprache:eng
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Zusammenfassung:A number of 3-isothiazolol bioisosteres of glutamic acid (1) and analogs of the AMPA receptor agonist, (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 2a), including (RS)-2-amino-3-(3-hydroxy-5-methylisothiazol-4-yl)propionic acid (thio-AMPA, 2b), were synthesized. Comparative in vitro pharmacological studies on this series of 3-isothiazolol and the corresponding 3-isoxazolol amino acids were performed using a series of receptor binding assays (IC50 values) and the electrophysiological rat cortical slice model (EC50 values). Whereas 2a (IC50 = 0.04 ± 0.005 μM, EC50 = 3.5 ± 0.2 μM) is markedly more potent than the tert-butyl analog ATPA (3a) (IC50 = 2.1 ± 0.16 μM, EC50 = 34 ± 2.4 μM) in [3H]AMPA binding and electrophysiological studies, 2b (IC50 = 1.8 ± 0.13 μM, EC50 = 15.0 ± 2.4 μM) was approximately equipotent with thio-ATPA (3b) (IC50 = 0.63 ± 0.07 μM, EC50 = 14 ± 1.3 μM). (RS)-2-Amino-3-(3-hydroxyisoxazol-5-yl)propionic acid (HIBO, 4a) was approximately equipotent with its thio analog 4b, whereas 4-Br-HIBO (5a) (IC50 = 0.65 ± 0.12 μM, EC50 = 22 ± 0.6 μM) turned out to be much more potent than the corresponding 3-isothiazolol 5b (IC50 = 17 ± 2.2 μM, EC50 = 500 ± 23 μM). 2b (ED50 = 130 μmol/kg) was more potent than 2a (220 μmol/kg) as a convulsant after subcutaneous administration in mice. The protolytic properties of 2a,b − 4a,b were determined using 13C NMR spectroscopy. For each pair of compounds, the α-amino acid groups showed similar protolytic properties, whereas the 3-isoxazolol moieties typically showed pK a values 2 units lower than those of the 3-isothiazolols. Accordingly, calculations of ionic species distributions revealed pronounced differences between 3-isoxazolol and 3-isothiazolol amino acids. No simple correlation between activity as AMPA agonists in vitro and pK a values of these compounds was apparent. On the other hand, the relative potencies of AMPA (2a) and thio-AMPA (2b) in vitro and in vivo may reflect that these compounds predominantly penetrate the blood−brain barrier as net uncharged diprotonated ionic species.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9607212