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

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.

7tm Receptors

“…Alexander et al Bräuner-Osborne H et al (1996) Gromoll et al, 1996;Beau et al, 1998;Touraine et al, 1999). Loss-of-function mutations of the LH receptor are associated with Leydig cell hypoplasia, and gain-of-function mutations are associated with male-limited gonadotropin-independent precocious puberty (e.g.…”

“…CPCCOEt (Litschig et al, 1999), BAY36-7620 (Carroll et al, 2001), LY456236 (Li et al, 2002), 3,5-DMPPP (Micheli et al, 2003, EM-TBPC (Malherbe et al, 2003) (Doherty et al, 1997), (S)-(+)-CBPG (Mannaioni et al, 1999) Homo-AMPA (Bräuner-Osborne et al, 1996), 1-benzyl-APDC (Tuckmantel et al, 1997) LSOP (Wu et al, 1998), L-AP4 LSOP (Wu et al, 1998) MAP4, THPG (Thoreson et al, 1997) -MPPG (Wu et al, 1998) Selective negative allosteric modulators SIB1757 (Varney et al, 1999), SIB1893 (Varney et al, 1999), MPEP (Gasparini et al, 1999b), MTEP (Brodkin et al, 2002), fenobam (Porter et al, 2005), YM298198 (Kohara et al, 2005) (Anderson et al, 2002) at mGlu5 receptors. Although a number of radioligands have been used to examine binding using native tissues, correlation with individual subtypes is limited.…”

Glutamate receptor ligands: Synthesis, stereochemistry, and enantiopharmacology of methylated 2‐aminoadipic acid analogs

“…1) is an agonist at NMDA receptors, 7 mGluR2 as well as at mGluR6, 8 whereas (R)-AA (2b) is inactive at the mGluRs but is a competitive antagonist at ionotropic NMDA receptors. 8,9 Furthermore, (S)-Glu analogs with a methyl substituent in the 4-position of the carbon backbone exhibit interesting pharmacology at KA receptors. (2S,4R)-4-Methyl-Glu (3a) is approximately 50-fold more potent at the KA receptors compared to (S)-Glu (1), whereas the 2S,4S- stereoisomer (3b), is less potent.…”

“…Compound 9 was prepared from (E)-2-pentenoic acid (8) Methyl 3-methyl-2-butenoate (15). Acetyl chloride (25 ml) was slowly added to ice-cold MeOH (200 ml) and 3-methyl-2-butenoic acid (14) (20 g, 200 mmol) dissolved in MeOH (50 ml) was then added to the solution.…”

Ligand-gated Ion Channels

“…Selective agonists CHPG (Doherty et al, 1997), (S)-(+)-CBPG (Mannaioni et al, 1999) Homo-AMPA (Bräuner-Osborne et al, 1996), 1-benzyl-APDC (Tuckmantel et al, 1997) LSOP (Wu et al, 1998), L-AP4 LSOP (Wu et al, 1998), L-AP4, (S)-3,4-DCPG (Thomas et al, 2001) (Wu et al, 1998) Selective negative allosteric modulators SIB1757 (Varney et al, 1999), SIB1893 (Varney et al, 1999), MPEP (Gasparini et al, 1999b), MTEP (Brodkin et al, 2002), fenobam (Porter et al, 2005) (S)-(+)-CBPG is an antagonist at mGlu1, but is an agonist (albeit of reduced efficacy) at mGlu5 receptors. DCG-IV also exhibits agonist activity at NMDA glutamate receptors (Uyama et al, 1997).…”