AMPA-RECEPTOR AGONISTS - RESOLUTION, CONFIGURATIONAL ASSIGNMENT, AND PHARMACOLOGY OF 3-[3-HYDROXY-5-(2-PYRIDYL)ISOXAZOL-4-YL]-PROPIONIC AND3-[3-HYDROXY-5-(2-PYRIDYL)ISOXAZOL-4-YL]-PROPIONIC ACID (2-PY-AMPA)())

We have previously shown that whereas (RS)-2-amino-3-(3-hydroxy-5-phen ylisoxazol-4-yl) propionic acid (APPA) shows the characteristics of a partial agonist at (RS)-2-amino-3-(3-hydroxy-5-methyrisoxazol-4-yl) pr opionic acid (AMPA) receptors, (S)-APPA is a full AMPA receptor agonis t and (R)-APPA a weak competitive AMPA receptor antagonist. This obser vation led us to introduce the new pharmacological concept, functional partial agonism. Recently we have shown that the 2-pyridyl analogue o f APPA, (RS)-2-amino-3-[3-hydroxy-5-(2-pyridyl) isoxazol-4-yl] propion ic acid (2-Py-AMPA), is a potent and apparently full AMPA receptor ago nist, and this compound has now been resolved into (+)- and (-)-2-Py-A MPA (ee greater than or equal to 99.0%) by chiral HPLC using a Chirobi otic T column. The absolute stereochemistry of the enantiomers of APPA has previously been established by X-ray analysis, and on the basis o f comparative studies of the circular dichroism spectra of the enantio mers of APPA and 2-Py-AMPA, (+)- and (-)-2-Py-AMPA were assigned the ( S)- and (R)-configuration, respectively. In a series of receptor bindi ng studies, neither enantiomer of 2-Py-AMPA showed detectable affinity for kainic acid receptor sites or different sites at the N-methyl-D-a spartic acid (NMDA receptor complex. (+)-(S)-2-Py-AMPA was an effectiv e inhibitor of [H-3]AMPA binding (IC50 = 0.19 +/- 0.06 mu M) and a pot ent AMPA receptor agonist in the rat cortical wedge preparation (EC50 = 4.5 +/- 0.3 mu M) comparable With AMPA (IC50 = 0.040 +/- 0.01 mu M; EC50 = 3.5 +/- 0.2 mu M), but much more potent than (+)-(S)-APPA (IC50 = 5.5 +/- 2.2 mu M) EC50 = 230 +/- 12 mu M). Like (-)-(R)-APPA (IC50 > 100 mu M), (-)-(R)-2-Py-AMPA (IC50 > 100 mu M) did not significantly affect [H-3]AMPA binding, and both compounds were weak AMPA receptor antagonists;(K-i = 270 +/- 50 and 290 +/- 20 mu M, respectively). Chir ality 9:274-280, 1997. (C) 1997 Wiley-Liss, Inc.