ISSN:
0899-0042
Keywords:
chiral HPLC
;
resolution
;
enantiomeric purity
;
configurational assignment
;
circular dichroism
;
AMPA receptor affinity
;
electrophysiology
;
AMPA receptor agonism
;
Chemistry
;
Organic Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
We have previously shown that whereas (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA) shows the characteristics of a partial agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, (S)-APPA is a full AMPA receptor agonist and (R)-APPA a weak competitive AMPA receptor antagonist. This observation led us to introduce the new pharmacological concept, functional partial agonism. Recently we have shown that the 2-pyridyl analogue of APPA, (RS)-2-amino-3-[3-hydroxy-5-(2-pyridyl)isoxazol-4-yl]propionic acid (2-Py-AMPA), is a potent and apparently full AMPA receptor agonist, and this compound has now been resolved into (+)- and (-)-2-Py-AMPA (ee ≥ 99.0%) by chiral HPLC using a Chirobiotic T column. The absolute stereochemistry of the enantiomers of APPA has previously been established by X-ray analysis, and on the basis of comparative studies of the circular dichroism spectra of the enantiomers of APPA and 2-Py-AMPA, (+)- and (-)-2-Py-AMPA were assigned the (S)- and (R)-configuration, respectively. In a series of receptor binding studies, neither enantiomer of 2-Py-AMPA showed detectable affinity for kainic acid receptor sites or different sites at the N-methyl-D-aspartic acid (NMDA) receptor complex. (+)-(S)-2-Py-AMPA was an effective inhibitor of [3H]AMPA binding (IC50 = 0.19 ± 0.06 μM) and a potent AMPA receptor agonist in the rat cortical wedge preparation (EC50 = 4.5 ± 0.3 μM) comparable with AMPA (IC50 = 0.040 ± 0.01 μM; EC50 = 3.5 ± 0.2 μM), but much more potent than (+)-(S)-APPA (IC50 = 5.5 ± 2.2 μM; EC50 = 230 ± 12 μM). Like (-)-(R)-APPA (IC50 〉 100 μM), (-)-(R)-2-Py-AMPA (IC50 〉 100 μM) did not significantly affect [3H]AMPA binding, and both compounds were week AMPA receptor antagonists (Ki = 270 ± 50 and 290 ± 20 μM, respectively). Chirality 9:274-280, 1997. © 1997 Wiley-Liss, Inc.
Additional Material:
7 Ill.
Type of Medium:
Electronic Resource
