Sulfate esters of hydroxy amino acids as stereospecific glutamate receptor agonists

Abstract

Enantiomerically pure sulfate esters of the hydroxy amino acids homserine, hydroxyproline and 4-hydroxypipecolic acid were synthesized and tested on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) 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 ligands (either agonists) for excitory 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 μM for NMDA and 300 μM for AMPA receptors and in the myenteric plexus its EC 50 was 600 μM. The stereoisomer R-homoserine sulfate did not depolarize the cortical wedges and failed to cause ileal contraction up to a concentration of 500 μM. 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 μM in the cortex. The other three isomers were not active as agonists up to 500 μM and none of them had antagonist activity. Finally, t-4- rmhydroxy- 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 μM in the cortex and 250 μM in the myenteric plexus. The cis-stereoisomer was significantly less potent (EC 50 75 μM in the cortex and no activity up to 500 μM 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 agonists in a stereospecific and selective manner with ionotropic glutamate receptors.