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

Enantiomerically pure sulfate esters of the hydroxy amino acids homose rine, hydroxyproline and 4-hydroxypipecolic acid were synthesized and tested on alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (N MDA) and N-methyl-D-aspartate (NMDA) receptors present in the mice cor tical wedge preparation and on NMDA receptors present in the myenteric plexus of the guinea pig with the aim of finding new possible endogen ous ligands (either agonists or antagonists) for excitatory amino acid receptors. The linear and flexible compound S-homoserine sulfate caus ed 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 AM PA receptors and in the myenteric plexus its EC(50) was 600 mu M. The stereoisomer R-homoserine sulfate did not depolarize the cortical wedg es and failed to cause ileal contraction up to a concentration of 500 mu M. Among the four possible stereoisomers of 4-hydroxyproline sulfat e, which are rigid structures and may be regarded as cyclization forms of homoserine sulfate, t-S-hydroxyproline sulfate was a selective AMP A 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 t hem had antagonist activity. Finally, t-4-hydroxy-S-pipecolic acid-4-s ulfate, a superior homologue of t-S-hydroxyproline sulfate, was found to be one of the most potent and selective NMDA receptor agonists so f ar 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 pote nt (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-hydroxypr oline sulfate and t-4-hydroxy-S-pipecolic acid-4-sulfate are natural c ompounds able to interact as agonists in a stereospecific and selectiv e manner with ionotropic glutamate receptors.