1 The depressant actions on evoked electrical activity and the excitant amino acid antagonist properties of a range of w-phosphonic x-carboxylic amino acids have been investigated in the isolated spinal cord preparations of the frog or immature rat. 2 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. 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.

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SUMMARY1. The depressant actions of Mg2+ and a range of other divalent ions on synaptic excitation and on responses produced by excitatory amino acids and other putative transmitters have been investigated in hemisected isolated spinal cords of frogs and neonatal rats. Some comparative studies were also made using the rat isolated superior cervical ganglion.2. At concentrations above 10 UM, Mg2+ selectively antagonized N-methyl-Daspartate (NMDA)-induced motoneurone depolarization as recorded from ventral roots of tetrodotoxin-blocked spinal cords. Depolarization evoked by quisqualate (unaffected by 20 mM-Mg2+) was resistant to the depressant action of these ions, while depolarizations evoked by other excitant amino acids were depressed to intermediate degrees.3. Mn2+, Co2+ and Ni2+ had qualitatively similar actions to Mg2+; Mn2+ was somewhat less potent and Co2+ and Ni2+ more potent than Mg2+. The alkaline earth metal ions, Ca2+, Sr2+ and Ba2+, had very weak Mg2+-like actions. Ca2+ and Mg2+ acted additively in depressing amino acid-induced responses.4. Mg2+ also depressed motoneurone responses evoked by noradrenaline, substance P and carbachol in the neonatal rat isolated spinal cord. However, none of these effects were as marked as the depression of NMDA-induced responses by Mg2 + in this preparation. Mg2+ did not depress motoneurone depolarization produced by 5-HT in the rat spinal cord or the depolarizing action of GABA on primary afferent terminals of the isolated frog spinal cord.5. At concentrations producing marked depression of NMDA-induced responses, Mg2+ also depressed synaptic transmission in spinal cords in the absence of an effect on ganglionic transmission. At the same concentrations, Mn2+, Co2+ and Ni2+ depressed synaptic transmission in both preparations.6. From the similarity in action between Mg2+ and the D-a-aminoadipate group of NMDA antagonists, it is suggested that the central depressant action of low concentrations of Mg2+ involves predominantly a postsynaptically mediated interference with the action of an excitatory amino acid transmitter.

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In the isolated frog or rat spinal cord, low concentrations of Mg2+ (0.5-1.00 mM) markedly depress, in a substantially Ca2+-independent manner, ventral root depolarizations produced by dorsal root stimulation and by certain amino acids (e.g. N-methyl-D-aspartate and L-homocysteate) but do not depress depolarizations produced by other excitatory amino acids (e.g. kainate and quisqualate). L-Aspartate-induced depolarizations are more sensitive to Mg2+ then are L-glutamate-induced depolarizations.

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A series of piperidine dicarboxylates (PDA) has been tested for excitatory amino acid agonist and antagonist activity and for synaptic depressant properties of the spinal cords of frogs and immature rats in vitro and of cats in vivo. The substances tested comprised (+/-)-cis-2,3-PDA, (+/-)-cis-2,4-PDA, (+/-)-cis-2,5-PDA, (+/-)-cis-2,6-PDA, (+/-)-trans-2,3-PDA, (+/-)-trans-2,4-PDA and both (+) and (-) forms of cis-2,3-PDA. Peak excitatory amino acid agonist activity was observed with (+/-)-trans-2,3- and (+/-)-trans-2,4-PDA. Excitatory amino acid antagonism and synaptic depressant activity was observed only with cis-dicarboxylates, this activity being greatest in the 2,3-analogue. The agonist actions of piperidine dicarboxylates were effectively depressed by the specific NMDA receptor antagonist, (-)-2-amino-5-phosphonovalerate and, where tested, also by D-alpha-aminoadipate and low concentrations of Mg2+. It was concluded that the major part of these agonist actions were mediated by NMDA receptors. The main structural feature of the NMDA agonist actions of these substances was considered to be their close relationship to N-alkyl-aspartic and glutamic acid molecules, with the trans arrangement of the respective 2,3- and 2,4-situated carboxyl groups promoting most effective interaction with the active sites of the NMDA receptor. (+/-)-Cis-2,3-PDA depressed excitatory responses induced by NMDA, kainate, quisqualate, (+/-)-trans-2,3-PDA and (+/-)-trans-2,4-PDA, or evoked by dorsal root stimulation. Both monosynaptic and polysynaptic excitation were susceptible to the depressant action of this substance. The (-) isomer of cis-2,3-PDA carried both excitatory amino acid agonist and antagonist activity and also the synaptic depressant properties observed with the racemic form of this substance. The (+) isomer showed little pharmacological activity. It is proposed that the structure-activity features of these heterocyclic amino acids indicate some of the conformational requirements for interaction with physiological excitatory amino acid receptors.