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Resolution, configurational assignment, and enantiopharmacology at glutamate receptors of 2‐amino‐3‐(3‐carboxy‐5‐methyl‐4‐isoxazolyl)propionic acid (ACPA) and demethyl‐ACPA
Author(s) -
Johansen Tommy N.,
Stensbøl Tine B.,
Nielsen Birgitte,
Vogensen Stine B.,
Frydenvang Karla,
Sløk Frank A.,
Brünum;unerOsborne Hans,
Madsen Ulf,
KrogsgaardLarsen Povl
Publication year - 2001
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/chir.1172
Subject(s) - ampa receptor , chemistry , agonist , receptor , kainic acid , enantiomer , stereochemistry , glutamate receptor , metabotropic glutamate receptor , nmda receptor , chiral column chromatography , biochemistry
We have previously described (RS)‐2‐amino‐3‐(3‐carboxy‐5‐methyl‐4‐isoxazolyl)propionic acid (ACPA) as a potent agonist at the (RS)‐2‐amino‐3‐(3‐hydroxy‐5‐methyl‐4‐isoxazolyl)propionic acid (AMPA) receptor subtype of (S)‐glutamic acid (Glu) receptors. We now report the chromatographic resolution of ACPA and (RS)‐2‐amino‐3‐(3‐carboxy‐4‐isoxazolyl)propionic acid (demethyl‐ACPA) using a Sumichiral OA‐5000 column. The configuration of the enantiomers of both compounds have been assigned based on X‐ray crystallographic analyses, supported by circular dichroism spectra and elution orders on chiral HPLC columns. Furthermore, the enantiopharmacology of ACPA and demethyl‐ACPA was investigated using radioligand binding and cortical wedge electrophysiological assay systems and cloned metabotropic Glu receptors. (S)‐ACPA showed high affinity in AMPA binding (IC 50 = 0.025 μM), low affinity in kainic acid binding (IC 50 = 3.6 μM), and potent AMPA receptor agonist activity on cortical neurons (EC 50 = 0.25 μM), whereas (R)‐ACPA was essentially inactive. Like (S)‐ACPA, (S)‐demethyl‐ACPA displayed high AMPA receptor affinity (IC 50 = 0.039 μM), but was found to be a relatively weak AMPA receptor agonist (EC 50 = 12 μM). The stereoselectivity observed for demethyl‐ACPA was high when based on AMPA receptor affinity (eudismic ratio = 250), but low when based on electrophysiological activity (eudismic ratio = 10). (R)‐Demethyl‐ACPA also possessed a weak NMDA receptor antagonist activity (IC 50 = 220 μM). Among the enantiomers tested, only (S)‐demethyl‐ACPA showed activity at metabotropic receptors, being a weak antagonist at the mGlu 2 receptor subtype (K B = 148 μM). Chirality 13:523–532, 2001. © 2001 Wiley‐Liss, Inc.