A NEW HIGHLY SELECTIVE METABOTROPIC EXCITATORY AMINO-ACID AGONIST - 2-AMINO-4-(3-HYDROXY-5-METHYLISOXAZOL-4-YL)BUTYRIC ACID

The homologous series of acidic amino acids, ranging from aspartic aci d (1) to 2-aminosuberic acid (5), and the corresponding series of 3-is oxazolol bioisosteres of these amino acids, ranging from -2-amino-2-(3 -hydroxy-5-methylisoxazol-4-yl)acetic acid (AMAA, 6) to -amino-6-(3-hy droxy-5-methylisoxazol-4-yl)hexanoic acid (10), were tested as ligands for metabotropic excitatory amino acid receptors (mGlu(1 alpha), mGlu (2), mGlu(4a), and mGlu(6)). Whereas AMAA (6) and amino-3-(3-hydroxy-5 -methylisoxazol-4-yl)propionic acid (AMPA, 7) are potent and highly se lective agonists at N-methyl-D-aspartic acid (NMDA) and AMPA receptors , respectively the higher homologue of AMPA (7), 2-amino-4-(3-hydroxy- 5-methylisoxazol-4-yl)butyric acid (homo-AMPA, 8), is inactive at iono tropic excitatory amino acid receptors. Homo-AMPA (8), which is a 3-is oxazolol bioisostere of 2-aminoadipic acid (3), was, however, shown to be a specific and rather potent agonist at mGlu(6), approximately 4 t imes weaker than the nonselective excitatory amino acid receptor agoni st (S)-glutamic acid. 2-Aminoadipic acid (3), which shows a complex ex citatory amino acid synaptic pharmacology, was an agonist at mGlu(6) a s well as mGlu(2). AMPA (7) and the higher homologue of homo-AMPA (8), amino-5-(3-hydroxy-5-methylisoxazol-4-yl)pentanoic acid (9), showed r elatively weak agonist effects at mGlu(6). It is concluded that homo-A MPA (8) is likely to be a useful tool for studies of the pharmacology and physiological role of mGlu(6). We describe a new versatile synthes is of this homologue of AMPA and the synthesis of compound 10.