Ibotenic acid analogues. Synthesis and biological and in vitro activity of conformationally restricted agonists at central excitatory amino acid receptors.

A number of analogues of ibotenic acid [(RS)-3-hydroxy-5- isoxazoleglycine ] were synthesized; they were tested as excitants on neurons in the cat spinal cord, by using microelectrophoretic techniques, and as inhibitors of the binding of kainic acid (KA) in vitro, by using synaptic membranes prepared from rat brains. The excitatory effects of the 3- isoxazolol amino acids (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5, 4-c]pyridine-7-carboxylic acid (4, 7- HPCA ), (RS)-alpha-amino-3-hydroxy-5,6-dihydro-4H- cyclohept [1,2-d] isoxa zole - 8-propionic acid (8, 8- AHCP ), (RS)-alpha-amino-3- hydroxy-7,8-dihydro-6H- cyclohept [1,2-d] isoxazole -4-propionic acid (12, 4- AHCP ), and (RS)-alpha-(methylamino)-3-hydroxy-5-methyl- 4- isoxazolepropionic acid (15, N-Me-AMPA) were shown to be sensitive to (S)-glutamic acid diethyl ester (GDEE), an antagonist at quisqualic acid ( QUIS ) receptors, and insensitive to (RS)-2-amino-5-phosphonovaleric acid ( 2APV ), an antagonist at N-methyl-(R)-aspartic acid (NMDA) receptors. The compounds 4 and 12 proved to be particularly potent agonists at the former class of receptor, assumed to represent physiological glutamic acid receptors. The amino acids (RS)-beta-(2-carboxyphenyl)alanine (19), an analogue of 12, and (RS)-2-(3-carboxyphenyl) glycine were weak GDEE-sensitive excitants with potencies comparable with that of 8. All of the compounds were tested as inhibitors of KA binding. With the exception of 12 and 19, which showed very low affinity for the KA binding sites, the compounds studied were inactive in this in vitro test system.