Possible NMDA antagonist properties of drugs that affect high pressure neurological syndrome

Abstract

1 Previous studies have suggested that a series of drugs modelled on part of the strychnine molecule interfere with the development of high pressure neurological syndrome (HPNS) and it was presumed that this effect was via an action on inhibitory glycinergic transmission. We have now used the rat hippocampal slice preparation to examine the possibility that some of these drugs might instead have an action at the strychnine-insensitive (SI) glycine binding site associated with the NMDA receptor. 2 D-2-Amino-5-phosphonovalerate (AP5) and 7-chlorokynurenate (7CK) had no significant effect on the height of the population spike recorded from the CAl region in 1 mM Mg2' medium, but both blocked the multiple population spikes recorded in Mg2+-free medium. The effect of 7CK, but not AP5, was reversed by 200fLM D-serine which is consistent with the known antagonist action of 7CK at the SI-glycine site. 3 A derivative of benzimidazole, which shows the clearest structural similarities to known SI-glycine site antagonists and ameliorates HPNS, mirrored the effects of 7CK although it was considerably less potent. 4 Gramine, which exacerbates HPNS, significantly increased the number of population spikes evoked in Mg2+-free medium. 5 Mephenesin, which is the most potent known drug in ameliorating HPNS, had no significant effect on the response recorded in 1 mM Mg2' and significantly reduced the number of population spikes recorded in Mg2+-free medium, but this effect was only partially reversed by the addition of D-serine.6 The results are consistent with the benzimidazole derivative, but not gramine, being an antagonist at the SI-glycine receptor. The results with mephenesin are equivocal but leave open the possibility that some of the drugs which are effective against HPNS act via an effect on excitatory NMDA receptormediated transmission, rather than on inhibitory glycine-mediated transmission.

Endogenous activation of presynaptic NMDA receptors enhances glutamate release from the primary afferents in the spinal dorsal horn in a rat model of neuropathic pain

“…It could be possible that ambient d ‐serine levels in normal conditions are not high enough to induce a sufficient number of activated NMDARs. In the following experiments, we recorded a pair of EPSCs evoked by a pair of electrical stimuli before and during perfusion of d ‐serine (200 μ m ) (Gaiarsa et al 1990; Shuker et al 1994; Li & Han, 2007) in spinal slices of sham‐operated rats. We found that bath perfusion of d ‐serine (200 μ m ) plus NMDA (50 μ m ) did not change either the EPSC amplitude or PPR in neurons ( n = 7) from sham‐operated rats (Fig.…”

Kinetics and mechanism of oxidation of the drug mephenesin by bis(hydrogenperiodato)argentate(III) complex anion

“…A later study provided evidence that mephenesin could be an antagonist of excitatory amino acids [2]. Shuker and coworkers [3] went on to hypothesize that this antagonistic effect on amino acids could be the reason for mephenesin's ability to act as a muscle relaxant. Not surprisingly, on the other hand, mephenesin also has drawbacks including that the muscle-relaxant effect only lasts for a short time, because the drugs are being rapidly metabolized.…”