Synthesis and pharmacology of 3-isoxazolol amino acids as selective antagonists at group I metabotropic glutamic acid receptors

Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid li gands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (iGluRs) , the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic aci d [HIBO, (RS)-4] so far known typically interact with iGluRs as well as met abotropic Glu receptors (mGluRs). We here report the synthesis and pharmaco logy of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 w as shown to be an antagonist at group I mGluRs. The effects of 9 were shown to reside exclusively in (S)-9 (K-b = 30 muM at mGlu(1) and K-b = 61 muM a t mGlu(5)). The lower homologue of 9, compound 8, showed comparable effects at mGluRs, but 8 also was a weak agonist at the AMPA subtype of iGluRs. Li ke 9, the higher homologue, compound 10, did not interact with iGluRs, but 10 selectively antagonized mGlu(1) (K-b = 160 muM) showing very weak antago nist effect at mGlu(5) (K-b = 990 muM). The phenyl analogue 11 turned out t o be an AMPA agonist and an antagonist at mGlu(1) and mGlu(5), and these ef fects were shown to originate in (S)-11 (EC50 = 395 muM, K-b = 86 and 90 mu M, respectively). Compound 9, administered icy, but not sc, was shown to pr otect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments of the enantiomers were based on X-ray crystallographic analys es.