SULFATE ESTERS OF HYDROXY AMINO-ACIDS AS STEREOSPECIFIC GLUTAMATE-RECEPTOR AGONISTS

Enantiomerically pure sulfate esters of the hydroxy amino acids homoserine, hydroxyproline and 4-hydroxypipecolic acid were synthesized and tested on alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (NMDA) and N-methyl-D-aspartate (NMDA) receptors present in the mice cortical wedge preparation and on NMDA receptors present in the myenteric plexus of the guinea pig with the aim of finding new possible endogenous ligands (either agonists or antagonists) for excitatory amino acid receptors. The linear and flexible compound S-homoserine sulfate caused a depolarization of both AMPA and NMDA receptors. In the cortex its agonist action had an EC(50) of 150 mu M for NMDA and 300 mu M for AMPA receptors and in the myenteric plexus its EC(50) was 600 mu M. The stereoisomer R-homoserine sulfate did not depolarize the cortical wedges and failed to cause ileal contraction up to a concentration of 500 mu M. Among the four possible stereoisomers of 4-hydroxyproline sulfate, which are rigid structures and may be regarded as cyclization forms of homoserine sulfate, t-S-hydroxyproline sulfate was a selective AMPA receptor agonist with an EC(50) of 70 mu M in the cortex. The other three isomers were not active as agonists up to 500 mu M and none of them had antagonist activity. Finally, t-4-hydroxy-S-pipecolic acid-4-sulfate, a superior homologue of t-S-hydroxyproline sulfate, was found to be one of the most potent and selective NMDA receptor agonists so far described with an EC(50) of 0.7 mu M in the cortex and 250 mu M in the myenteric plexus. The cis-stereoisomer was significantly less potent (EC(50) 75 mu M in the cortex and no activity up to 500 mu M in the myenteric plexus). In conclusion, S-homoserine sulfate, t-S-hydroxyproline sulfate and t-4-hydroxy-S-pipecolic acid-4-sulfate are natural compounds able to interact as agonists in a stereospecific and selective manner with ionotropic glutamate receptors.