HETEROARYL ANALOGS OF AMPA - 2 - SYNTHESIS, ABSOLUTE STEREOCHEMISTRY,PHOTOCHEMISTRY, AND STRUCTURE-ACTIVITY-RELATIONSHIPS

We have previously shown that amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl )propionic acid [(S)-APPA, 2] is a weak agonist at amino-3-(3-hydroxy- 5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors, specifically ac tivated by (S)-AMPA (1), whereas -3-[3-hydroxy-5-(2-pyridyl)-4-isoxazo lyl]propionic acid [(S)-2-Py-AMPA, 5] and -[3-hydroxy-5-(2-thiazolyl)- 4-isoxazolyl]propionic acid (4) are potent AMPA agonists. On the other hand, (R)-APPA (3) and (R)-2-Py-AMPA (6) have been shown to be weak A MPA antagonists. We now report the synthesis of 2-Py-AMPA (7a) and the isomeric compounds 3-Py-AMPA (7b) and 4-Py-AMPA (7c) as well as the 7 a analogues, roxy-5-(6-methyl-2-pyridyl)-4-isoxazolyl]propionic acid ( 7d) and (RS)-2-amino-3-[3-hydroxy-5-(2-quinolinyl)-4- isoxazolyl]propi onic acid (7e). Furthermore, no-3-[3-hydroxy-5-(2-furyl)-4-isoxazolyl] propionic acid (2-Fu-AMPA, 7f) and its 5-bromo-2-furyl derivative (7g) were synthesized, and (S)-2-Fu-AMPA (8) and (R)-2-Fu-AMPA (9) were pr epared by semipreparative chiral HPLC resolution of 7f. HPLC analyses and circular dichroism spectroscopy indicated the absolute stereochemi stry of 8 and 9 to be S and R, respectively. This was confirmed by an X-ray crystallographic analysis of 9 HCl. In receptor binding (IC50 va lues) and rat cortical wedge electrophysiological (EC50 values) studie s, 7c (IC50 = 5.5 +/- 0.6 mu M; EC50 = 96 +/- 5 mu M) was shown to be markedly weaker than 7a (IC50 = 0.57 +/- 0.16 mu M; EC50 = 7.4 +/- 0.2 mu M) as an AMPA agonist, whereas 7b,d,e were inactive. The very pote nt AMPA agonist effect of 7f (IC50 = 0.15 +/- 0.03 mu M; EC50 = 1.7 +/ - 0.2 mu M) was shown to reside exclusively in 8 (IC50 = 0.11 +/- 0.01 mu M; EC50 = 0.71 +/- 0.11 mu M), whereas 9 did not interact signific antly with AMPA receptors, either as an agonist or as an antagonist. 8 was shown to be photochemically active and is a potential photoaffini ty label for the recognition site of the AMPA receptors. Compound 7g t urned out to be a very weak AMPA receptor agonist (IC50 = 12 +/- 0.7 m u M; EC50 = 160 +/- 15 mu M). None of these new compounds showed detec table effects at N-methyl-D-aspartic acid (NMDA) or kainic acid recept ors in vitro. The present studies have emphasized that the presence of a heteroatom in the 2-position of the heteroaryl 5-substituent greatl y facilitates AMPA receptor agonist activity.