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 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 microM, EC50 = 3.5 +/- 0.2 microM) is markedly more potent than the tert-butyl analog ATPA (3a) (IC50 = 2.1 +/- 0.16 microM, EC50 = 34 +/- 2.4 microM) in [3H]AMPA binding and electrophysiological studies, 2b (IC50 = 1.8 +/- 0.13 microM, EC50 = 15.0 +/- 2.4 microM) was approximately equipotent with thio-ATPA (3b) (IC50 = 0.63 +/- 0.07 microM, EC50 = 14 +/- 1.3 microM). (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 microM, EC50 = 22 +/- 0.6 microM) turned out to be much more potent than the corresponding 3-isothiazolol 5b (IC50 = 17 +/- 2.2 microM, EC50 = 500 +/- 23 microM). 2b (ED50 = 130 mumol/kg) was more potent than 2a (220 mumol/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 alpha-amino acid groups showed similar protolytic properties, whereas the 3-isoxazolol moieties typically showed pKa 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 pKa 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.
Matzen
L
L
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Engesgaard
A
A
Ebert
B
B
Didriksen
M
M
Frølund
B
B
Krogsgaard-Larsen
P
P
Jaroszewski
J W
JW
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry; D018698:Glutamic Acid / Q000031:analogs & derivatives*; D051379:Mice; D016202:N-Methylaspartate / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists*; D018092:Kainic Acid Receptors / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000737:chemistry / Q000494:pharmacology
D000927:Anticonvulsants; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D013844:Thiazoles; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C001490:3-isothiazolone