THE EFFECTS OF A SERIES OF ω‐PHOSPHONIC α‐CARBOXYLIC AMINO ACIDS ON ELECTRICALLY EVOKED AND EXCITANT AMINO ACID‐INDUCED RESPONSES IN ISOLATED SPINAL CORD PREPARATIONS

Abstract

The depressant actions on evoked electrical activity and the excitant amino acid antagonist properties of a range of ω‐phosphonic α‐carboxylic amino acids have been investigated in the isolated spinal cord preparations of the frog or immature rat. When tested on dorsal root‐evoked ventral root potentials, members of the homologous series from 2‐amino‐5‐phosphonovaleric acid to 2‐amino‐8‐phosphonooctanoic acid showed depressant actions which correlated with the ability of the substances to antagonize selectively motoneuronal depolarizations induced by N‐methyl‐d‐aspartate. 2‐Amino‐5‐phosphonovalerate was the most potent substance of the series giving an apparent KD of 1.4 μ m for the antagonism of responses to N‐methyl‐d‐aspartate. A comparison of the (+)‐ and (—)‐forms of 2‐amino‐5‐phosphonovalerate indicated that the N‐methyl‐d‐aspartate antagonist activity and the neuronal depressant action of this substance were both due mainly to the (—)‐isomer. The (—)‐ and (+)‐forms of 2‐amino‐4‐phosphonobutyrate had different actions. The (—)‐form of this substance had a relatively weak and non‐selective antagonist action on depolarizations induced by N‐methyl‐d‐aspartate, quisqualate and kainate and a similarly weak depressant effect when tested on evoked electrical activity. The (+)‐form was more potent than the (—)‐form in depressing electrically evoked activity but did not antagonize responses to amino acid excitants. At concentrations higher than those required to depress electrically evoked activity, the (+)‐form produced depolarization. This action was blocked by 2‐amino‐5‐phosphonovalerate.