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A New Highly Selective Metabotropic Excitatory Amino Acid Agonist: 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric Acid

A New Highly Selective Metabotropic Excitatory Amino Acid Agonist: 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric Acid

H Bräuner-Osborne, F A Sløk, N Skjaerbaek, B Ebert, N Sekiyama, S Nakanishi, P Krogsgaard-Larsen

J Med Chem. 1996 Aug 2;39(16):3188-94.

PMID: 8759641

Abstract:

The homologous series of acidic amino acids, ranging from aspartic acid (1) to 2-aminosuberic acid (5), and the corresponding series of 3-isoxazolol bioisosteres of these amino acids, ranging from (RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid (AMAA, 6) to (RS)-2-amino-6-(3-hydroxy-5-methylisoxazol-4-yl)hexanoic acid (10), were tested as ligands for metabotropic excitatory amino acid receptors (mGlu1 alpha, mGlu2, mGlu4a, and mGlu6). Whereas AMAA (6) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propinoic acid (AMPA, 7) are potent and highly selective agonists at N-methyl-D-aspartic acid (NMDA) and AMPA receptors, respectively, the higher homologue of AMPA (7), (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (homo-AMPA, 8), is inactive at ionotropic excitatory amino acid receptors. Homo-AMPA (8), which is a 3-isoxazolol bioisostere of 2-aminoadipic acid (3), was, however, shown to be a specific and rather potent agonist at mGlu6, approximately 4 times weaker than the nonselective excitatory amino acid receptor agonist (S)-glutamic acid. 2-Aminoadipic acid (3), which shows a complex excitatory amino acid synaptic pharmacology, was an agonist at mGlu6 as well as mGlu2. AMPA (7) and the higher homologue of homo-AMPA (8), (RS)-2-amino-5-(3-hydroxy-5-methylisoxazol-4-yl)pentanoic acid (9), showed relatively weak agonist effects at mGlu6. It is concluded that homo-AMPA (8) is likely to be a useful tool for studies of the pharmacology and physiological role of mGlu6. We describe a new versatile synthesis of this homologue of AMPA and the synthesis of compound 10.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1072951597	3,5-Diiodo-2-methoxyphenylboronic acid		1072951-59-7	Price
LS7931271	2,3-dihydrobenzofuran-5-boronic acid			Price

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