Phosphonate analogues of acidic amino acids: inhibition of excitatory amino acid transmitter binding to cerebellar membranes and of the stimulation of cerebellar cyclic GMP levels.

An examination was made of the ability of phosphonate analogues of acidic amino acids to interact with excitatory amino acid receptors, employing binding assays for [3H]glutamate and [3H]aspartate and by investigating the inhibitory effects of these compounds on the stimulation of cerebellar cyclic GMP levels. In both systems the phosphonates exhibited inhibitory activity, although the cGMP system corresponded better with electrophysiological data. The higher homologues (e.g. 2-amino-5-phosphonovalerate) showed high selectivity for NMDA-type receptors and this effect was stereospecific, with the (-)-isomers being at least 4-7 times more active than the (+)-forms.