Structure-activity relations of dipeptide antagonists of excitatory amino acids

Structure-activity relations of dipeptides related to gamma-D-glutamylglycine have been investigated with respect to the ability of these substances to antagonize depolarizing responses of frog motoneurones in vitro to N-methyl-D-aspartate, kainate and quisqualate. A terminal phosphono group was optimal for N-methyl-D-aspartate antagonist activity in relation to both potency and selectivity. Substances containing a terminal phosphono group were relatively poor antagonists of kainate or quisqualate responses. Terminal carboxylic and sulphonic groups were both effective with respect to kainate and/or quisqualate antagonism. Sulphonic compounds were the more selective in this type of action because of their low affinity for N-methyl-D-aspartate receptors. Optimum chain length for N-methyl-D-aspartate antagonism was between one and two carbon atoms shorter than for optimum kainate/quisqualate antagonist activity. Bulky groups within the N-acylated amino acid moiety generally, but differentially, reduced the ability of the substance to antagonize responses to each of the three agonists. Glutamyl peptides were generally more effective than aspartyl peptides of the same overall chain length. However, the most potent dipeptide (selective for N-methyl-D-aspartate antagonism) was the aspartyl derivative, beta-D-aspartylaminomethyl phosphonate, for which there was no glutamyl equivalent. Other useful substances to emerge from this study include the relatively selective kainate/quisqualate antagonists, gamma-D-glutamylaminomethyl sulphonate and gamma-D-glutamyltaurine. If similar selectivity is shown in other preparations also, these substances may prove preferable to gamma-D-glutamylglycine as antagonists of synaptic excitation mediated by kainate or quisqualate receptors.