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AMPA receptor agonists: Resolution, configurational assignment, and pharmacology of (+)‐(S)‐ and (‐)‐(R)‐2‐amino‐3‐[3‐hydroxy‐5‐(2‐pyridyl)‐isoxazol‐4‐yl]‐propionic acid (2‐Py‐AMPA)
Author(s) -
Johansen Tommy N.,
Ebert Bjarke,
Falch Erik,
KrogsgaardLarsen Povl
Publication year - 1997
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1997)9:3<274::aid-chir12>3.0.co;2-k
Subject(s) - ampa receptor , chemistry , agonist , partial agonist , nmda receptor , kainic acid , stereochemistry , enantiomer , nbqx , glutamate receptor , receptor , biochemistry
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 [ 3 H]AMPA binding (IC 50 = 0.19 ± 0.06 μM) and a potent AMPA receptor agonist in the rat cortical wedge preparation (EC 50 = 4.5 ± 0.3 μM) comparable with AMPA (IC 50 = 0.040 ± 0.01 μM; EC 50 = 3.5 ± 0.2 μM), but much more potent than (+)‐(S)‐APPA (IC 50 = 5.5 ± 2.2 μM; EC 50 = 230 ± 12 μM). Like (‐)‐(R)‐APPA (IC 50 > 100 μM), (‐)‐(R)‐2‐Py‐AMPA (IC 50 > 100 μM) did not significantly affect [ 3 H]AMPA binding, and both compounds were week AMPA receptor antagonists (K i = 270 ± 50 and 290 ± 20 μM, respectively). Chirality 9:274–280, 1997. © 1997 Wiley‐Liss, Inc.