Aryl and cycloalkyl analogues of AMPA: synthetic, pharmacological and stereochemical aspects

• Published in: Bioorganic & medicinal chemistry Vol. 6; no. 1; pp. 119 - 131
• Main Authors: Skjærbæk, Niels, Brehm, Lotte, Johansen, Tommy N., Hansen, Lene M., Nielsen, Birgitte, Ebert, Bjarke, Søby, Karina K., Stensbøl, Tine B., Falch, Erik, Krogsgaard-Larsen, Povl
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 1998
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - agonists; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - analogs & derivatives; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology; AMPA agonist; AMPA antagonist; Animals; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Circular Dichroism; conformational analysis; Corpus Callosum - drug effects; Corpus Callosum - metabolism; Dinucleoside Phosphates - chemistry; Dinucleoside Phosphates - pharmacology; Electrophysiology; Excitatory Amino Acid Agonists - chemical synthesis; Excitatory Amino Acid Agonists - pharmacology; Excitatory amino acid receptor; functional partial agonism; Molecular Conformation; Radioligand Assay; Rats; Receptors, AMPA - agonists; Receptors, AMPA - antagonists & inhibitors; Receptors, AMPA - drug effects; Stereoisomerism; Structure-Activity Relationship; functional partial agonism; AMPA antagonist; conformational analysis; Excitatory amino acid receptor; AMPA agonist
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(97)10017-7

We have previously shown that (
RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA,
2) is a functional partial agonist at the (
RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) subtype of excitatory amino acid receptors, reflecting that (
S)-APPA is a full agonist and (
R)-APPA a competitive antagonist at AMPA receptors. We have now synthesized and pharmacologically characterized (
RS)-2-amino-3-[3-hydroxy-5-(2-fluorophenyl)isoxazol-4-yl]propionic acid (2-F-APPA,
5a), 3-F-APPA (
5b), 4-F-APPA (
5c), (
S)-4-F-APPA (
6), (
R)-4-F-APPA (
7), and the fully and partially, respectively, saturated APPA (
2) analogues, (
RS)-2-amino-3-(hydroxy-5-cyclohexylisoxazol-4-yl)propionic acid (
5d) and compound
5e containing a 1-cyclohexenyl ring. The absolute stereo-chemistry of
6 and
7 was established on the basis of comparative circular dichroism studies on
6, 7, and (
S)- and (
R)-APPA. 4-F-APPA (
5c), (
S-4-F-APPA (
6),
5d, and
5e were shown to selectively inhibit [
3H]AMPA binding and to activate AMPA receptors. Whereas (
S)-4-F-APPA (
6) showed full AMPA receptor agonism, (
R)-4-F-APPA (
7) was an AMPA receptor antagonist. Co-administration of (
S)- and (
R)-4-F-APPA to the rat cortical wedge preparation produced functional partial AMPA receptor agonism. Semi empirical calculations showed that the magnitude of the torsional angle of the bond connecting the two rings in the series of nonannulated bicyclic AMPA analogues appears to be of importance for the potency and efficacy of these compounds.
Compound
5d is 15 times and
6 is four times weaker than
5e as selective AMPA receptor agonists, whereas
7 is an AMPA antagonist. Co-administration of
6 and
7, at different ratios, to the rat cortical wedge preparation produces functional partial agonism. The potency of these AMPA agonists appears to be dependent on the torsional angle of the two rings.