Synthesis and structure-activity studies on acidic amino acids and related diacids as NMDA receptor ligands.
The 3-isoxazolol amino acids (S)-2-amino-3-(3-hydroxy-5-methyl-4- isoxazolyl)propionic acid [(S)-AMPA, 2] and (R,S)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA, 5a) (Figure 1) are potent and specific agonists at the AMPA and N-methyl-D-aspartic acid (NMDA) subtypes, respectively, of (S)-glutamic acid (1) receptors. A number of amino acids and diacids structurally related to AMAA were synthesized and tested electrophysiologically and in receptor-binding assays. The hydroxymethyl analogue 7c of AMAA was an NMDA agonist approximately equipotent with AMAA in the [3H]CPP-binding assay (IC50 = 7 +/- 3 microM) and electropharmacologically in the rat cortical wedge model (EC50 = 8 +/- 2 microM). In contrast to this, the tertbutyl analogue 7a of AMAA turned out to be an antagonist at NMDA and AMPA receptors. The conformational characteristics of AMAA and 7a, c were studied by molecular mechanics calculations. Compound 7a possesses extra steric bulk and shows significant restriction of conformational flexibility compared to AMAA and 7c, which may be determining factors for the observed differences in biological activity. Although the nitrogen atom of quinolinic acid (6) has very weak basic character, 6 is a, perhaps subtype-selective, NMDA receptor agonist and a potent neurotoxic agent. These aspects prompted us to synthesize and test the diacids 8a, b, in which the amino group of AMAA has been replaced by a methylthio and methoxy group, respectively. Neither compound showed significant affinity for nor depolarizing effects at NMDA receptors. The hydroxymethyl AMPA analogue 3c showed no interaction with NMDA receptors and only weak AMPA agonist effects.
Johansen
T N
TN
PharmaBiotec Research Center, Royal Danish School of Pharmacy, Copenhagen.
Frydenvang
K
K
Ebert
B
B
Krogsgaard-Larsen
P
P
Madsen
U
U
D000085:Acetates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006860:Hydrogen Bonding; D007555:Isoxazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism / Q000494:pharmacology
C089706:2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid; D000085:Acetates; D007555:Isoxazoles; D008024:Ligands; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005998:Glycine