Glutamate receptor channels in rat DRG neurons: activation by kainate and quisqualate and blockade of desensitization by Con A.

Primary afferent C fibers in rat dorsal roots are depolarized by the excitatory amino acids kainate and domoate. Under whole-cell voltage clamp, kainate and domoate increase membrane conductance in a subpopulation of freshly dissociated DRG neurons. In contrast to kainate currents observed in CNS neurons, responses to kainate and domoate in DRG cells desensitize with prolonged agonist exposure. Half-maximal activation is achieved with much lower concentrations of kainate and domoate in sensory neurons than in CNS neurons from cerebral cortex. Rapid applications of glutamate, quisqualate, and AMPA evoke a transient current in DRG neurons and desensitize cells to subsequent applications of kainate or domoate. Brief incubation with the lectin concanavalin A eliminates desensitization to excitatory amino acids; after treatment with concanavalin A, all five agonists gate sustained currents of similar amplitude via the same receptor.

Involvement of accumulated NOS inhibitors and endothelin-1, enhanced arginase, and impaired DDAH activities in pulmonary dysfunction following subarachnoid hemorrhage in the rabbit.

We designed the present experiments to investigate the involvement of endogenous nitric oxide synthase (NOS) inhibitors, dimethylarginine dimethylaminohydrolase (DDAH) as a hydrolyzing enzyme of the NOS inhibitors, NOS, arginase which shares l-arginine as a common substrate with NOS, and endothelin-1 (ET-1) in the pulmonary dysfunction after induction of experimental subarachnoid hemorrhage (SAH) in the rabbit. SAH was induced by injecting autologous blood into the cisterna magna, and controls were injected with saline. On day 2, pulmonary arteries were isolated for determinations. A significant impairment of the endothelium-dependent relaxation (EDR) caused by acetylcholine was found in 20 cases (43.5%) out of 46 SAH animals, and the same animals exhibited accompanying the significantly impaired cyclic GMP production, accumulated endogenous NOS inhibitors, attenuated DDAH activity, enhanced arginase activity and accumulated ET-1 within the vessel wall. Meanwhile, there were no differences in endothelial NOS activity per se and sodium nitroprusside-induced relaxation between the animals with an impaired EDR and those without such a change. ET-1 content within aortic wall was increased with concomitant decrease in cyclic GMP production after the intraperitoneal application of authentic monomethylarginine as a NOS inhibitor in the rat. The current results suggest that accumulated endogenous NOS inhibitors and enhanced arginase activity possibly bring about the impaired NO production, thereby attenuating the EDR and contributing to the accumulation of ET-1 within the vessel wall. The accumulated endogenous NOS inhibitors at least partly result from the decreased DDAH activity. These alterations may be relevant to the pulmonary dysfunction after induction of SAH.

The anxiolytic-like effect of 5-HT1B receptor ligands in rats: a possible mechanism of action.

We have examined the effect of lesions of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 x 10 mg kg(-1)), and the influence of flumazenil (Ro 15-1788, 10 mg kg(-1)), a benzodiazepine receptor antagonist, on the anxiolytic-like activity of CP 94253 (5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine), a 5-HT1B receptor agonist, SB 216641 (N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide), a 5-HT1B receptor antagonist, and GR 127935 (N-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-l, l'-biphenyl-4-carboxamide), a 5-HT1B/1D receptor antagonist, in the Vogel conflict drinking test in rats. Diazepam was used as a reference compound. CP 94253 (2.5 mg kg(-1)), SB 216641 (2.5 mg kg(-1)), GR 127935 (10 mg kg(-1)) and diazepam (5 mg kg(-1)) significantly increased the number of shocks accepted during experimental sessions in the conflict drinking test in vehicle- and p-CA-pretreated rats. Flumazenil did not change the anxiolytic-like effect of CP 94253 (2.5 mg kg(-1)), but wholly blocked the anxiolytic-like effects of SB 216641 (2.5 mg kg(-1)), GR 127935 (10 mg kg(-1)) and diazepam (5 mg kg(-1)). p-CA and flumazenil alone were inactive in the conflict drinking test. The results suggested that the anxiolytic-like effect of the 5-HT1B receptor ligands CP 94253, SB 216641 and GR 127935 was possibly linked to the postsynaptic 5-HT1B receptors or/and 5-HT1B heteroreceptors. The results suggested also that benzodiazepine receptors were indirectly involved in the effects of SB 216641 and GR 127935 (but not of CP 94253), which might have been due to a possible interaction between the 5-HT and the GABA/benzodiazepine systems.

The pharmacology of quisqualate and AMPA in the cerebral cortex of the rat in vitro.

The depolarising population response to the excitatory amino acids, quisqualate and AMPA, in slices of cerebral cortex of the rat have been compared. Their respective dose-response curves had a similar maximum but the slope of the curve for AMPA was consistently steeper than that for quisqualate. The dose-response curves for AMPA had a mean log EC50 of -5.18 +/- 0.05, which was significantly different from -4.62 +/- 0.07 the mean log EC50 of the dose-response curves for quisqualate. Responses to both agonists were antagonised by kynurenic acid, barbiturates and gamma-DGT to a similar extent. The antagonism by kynurenate appeared to be competitive whilst the barbiturates were evidently noncompetitive antagonists. These results are in agreement with claims that quisqualate and AMPA act at a similar recognition site. The differences in the slopes of the dose-response curves for quisqualate and AMPA may be explained by the differences in the cellular uptake of the two agonists and/or by differences in efficacy.

A dipeptide derived from kainic and L-glutamic acids: a selective antagonist of amino acid induced neuroexcitation with anticonvulsant properties.

The dipeptide N-[[[2'S-(2' alpha, 3' beta, 4' beta)]-2'-carboxy-4'-(1"-methylethenyl)-3'-pyrrolidinyl)acetyl]-L- glutamic acid (6) has been synthesized by a route that involves the selective protection of the alpha-carboxyl function of kainic acid. This dipeptide inhibits the stimulation of Na+ fluxes induced in brain slices by the neuroexcitant N-methyl-D-aspartic acid. Administered intracerebroventricularly, it is also effective in protecting mice from picrotoxin-induced convulsions with an ED50 of 0.17 mumol.

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.

Comparison of sigma- and kappa-opiate receptor ligands as excitatory amino acid antagonists.

Using the technique of microelectrophoresis in pentobarbitone-anaesthetized cats and rats, the effects of benzomorphans, with known actions at sigma- and kappa- opioid receptors, were tested on responses of spinal neurones to amino acids and acetylcholine. The racemic mixture and both enantiomers of the sigma opiate receptor agonist, N-allylnormetazocine (SKF 10, 047), and the dissociative anaesthetic, ketamine, reduced or abolished excitation evoked by N-methyl-aspartate (NMA) with only small and variable effects on responses to quisqualate or kainate. (+)-SKF 10, 047 was 1.2 +/- 0.7 times more potent than the (-)-enantiomer in antagonizing NMA. On Renshaw cells, (+)-SKF 10, 047 enhanced responses to acetylcholine whereas the (-) enantiomer produced only a small reduction. The kappa- opiate receptor agonist, ethylketocyclazocine, had no selective effects on responses to amino acids or to acetylcholine. We conclude that actions at sigma- but not kappa-, opiate receptors are responsible for the NMA antagonism observed with benzomorphans.

Quinoxalinediones selectively block quisqualate and kainate receptors and synaptic events in rat neocortex and hippocampus and frog spinal cord in vitro.

1. Two quinozalinediones, FG9041 and FG9065, which had previously been shown to displace binding to the quisqualate receptor, were tested on rat neocortex and frog spinal cord in vitro against depolarizations induced by quisqualate, kainate and N-methyl-D-aspartate (NMDA). In both preparations effects of quisqualate were reduced the most and those of NMDA the least. 2. The near unitary slopes of the Schild plots were consistent with a competitive type of interaction. pA2 values for FG9041 were estimated to be 6.6, 6.1 and 5.1 in frog cord and 5.9, 5.3 and and about 4 in the rat neocortex for quisqualate, kainate and NMDA antagonism, respectively. FG9065 gave equivalent pA2 values of 6.2, 5.6 and 4.5. 3. At concentrations, which were without effect on depolarizations induced by NMDA, FG9041 and FG9065 reduced or blocked synaptically-evoked field potentials in hippocampal and neocortical slices superfused with normal magnesium-containing medium. Since these synaptic components are also insensitive to NMDA antagonists, these results are consistent with their mediation by postsynaptic receptors of the quisqualate (or kainate) type. 4. By contrast, quinoxalinediones had only limited effects on spontaneous epileptiform activity seen in both neocortical and hippocampal preparations when superfused with magnesium-free medium. These burst discharges were, however, abolished by NMDA antagonists. 5. In the frog spinal cord the early component of the dorsal root to ventral root reflexes was selectively reduced by FG9041 whereas NMDA antagonists reduced the longer latency components. 6. Our results suggest that the quinoxalinediones are likely to be useful pharmacological probes for elucidating the role of non-NMDA receptors in the vertebrate central nervous system.

Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling.

(1) The sensitivity of the particulate guanylate cyclase-cyclic guanosine-3',5'-monophosphate (cGMP) system to atrial (ANP) and C-type (CNP) natriuretic peptides was investigated in aortae and mesenteric small arteries from wild-type (WT) and endothelial nitric oxide synthase (eNOS) knockout (KO) mice. (2) ANP and CNP produced concentration-dependent relaxations of mouse aorta that were significantly attenuated by the natriuretic peptide receptor (NPR)-A/B antagonist HS-142-1 (10(-5) M). Both ANP and CNP were more potent in aortae from eNOS KO mice compared to WT. (3) The potency of ANP and CNP in aortae from WT animals was increased in the presence of the NOS inhibitor, N(G)-nitro-L-arginine (3 x 10(-4) M) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (5 x 10(-6) M). (4) In contrast, the potency of ANP and CNP in aortae from eNOS KO animals was reduced following pretreatment of tissues with supramaximal concentrations of the NO-donor, glyceryl trinitrate (3 x 10(-5) M, 30 min) or ANP (10(-7) M, 30 min). (5) Responses to acetylcholine in aortae from WT mice (dependent on the release of endothelium-derived NO) were significantly reduced following pretreatment of tissues with GTN (3 x 10(-5) M, 30 min) and ANP (10(-7) M, 30 min). (6) CNP and the NO-donor, spermine-NONOate caused concentration-dependent relaxations of mesenteric small arteries from WT animals that were significantly increased in eNOS KO mice compared to WT. ANP was unable to significantly relax mesenteric arteries from WT or eNOS KO animals. (7) In conclusion, both NPR-A- and NPR-B-linked pGC pathways are modulated by NO-cGMP in murine aorta and mesenteric small arteries and crossdesensitisation occurs between NPR subtypes. The biological activity of endothelium-derived NO is also influenced by the ambient concentration of NO and natriuretic peptides. Such an autoregulatory pathway may represent an important physiological homeostatic mechanism and link the paracrine activity of NO and CNP with the endocrine functions of ANP and BNP in the regulation of vascular tone and blood pressure.

Kynurenic acid distinguishes kainate and quisqualate receptors in the vertebrate retina.

Excitatory amino acid receptors (EAARs) underlie major synaptic pathways in the brain, retina and spinal cord. Several subclasses of EAARs have been proposed, based on pharmacological studies using a variety of agonists and antagonists. Kynurenic acid (Kyn), a metabolite of tryptophan, has been recently proposed as a potent EAAR antagonist. In this report, we show that Kyn can be used to separate two distinct classes of EAAR in the vertebrate retina: it blocks kainic acid (KA) responses but has minimal effects on responses mediated by quisqualate (QQ). At concentrations which block the KA responses, Kyn also blocks the light-evoked synaptic responses of all types of third-order neurons in the retina. These results suggest that KA receptors are the major receptor subtypes which underlie synaptic transmission and that QQ receptors are minimally utilized by light-activated pathways under the conditions of our experiments.

Anticonvulsant action of beta-kainic acid in mice. Is beta-kainic acid an N-methyl-D-aspartate antagonist?

An effect of the beta-stereoisomer of kainic acid on seizures produced by intracerebroventricular injections of excitatory amino acids was tested in mice. beta-Kainic acid preferentially antagonizes myoclonic seizures induced by N-methyl-D-aspartate and quinolinate, has less pronounced anticonvulsant action against alpha-kainate, D-homocysteinesulphinate and quisqualate, and no effect on convulsions induced by L-glutamate. The anticonvulsant activity of beta-kainic acid matches that of 2-amino-7-phosphonoheptanoic and kynurenic acids, both preferential N-methyl-D-aspartate receptor antagonists, and differs considerably from the profile of anticonvulsant action of gamma-D-glutamylaminomethylsulphonic acid, a preferential kainate/quisqualate antagonist.

The effect of the dioxolanes on amino acid induced excitation in the mammalian spinal cord.

The effects of the dissociative anaesthetic, etoxadrol, and the stereoisomers of dioxadrol, dexoxadrol and levoxadrol, were examined on the excitation of spinal neurones by electrophoretically administered amino acids in pentobarbitone- or urethane-anaesthetized rats, or pentobarbitone-anaesthetized cats. Both etoxadrol and the (+)isomer of dioxadrol, dexoxadrol, administered locally or systemically, exhibited a selective antagonism of N-methyl-D,L-aspartate relative to quisqualate and kainate. This selective antagonism was not observed with the (-)isomer of dioxadrol, levoxadrol. Since such a stereoselective antagonism of the excitation of spinal neurones by N-methyl-D,L-aspartate is also displayed by the dissociative anaesthetics phencyclidine and ketamine, it is suggested that a reduced efficiency at excitatory synapses utilising N-methyl-D,L-aspartate receptors contributes to that part of the pharmacological spectrum common to both arylcyclohexylamines and dioxolanes.

Quisqualic acid excitation of cortical neurones is selectively antagonized by streptomycin.

Although evidence exists for at least 3 kinds of excitatory amino acid receptor in the CNS, responding to N-methyl-D-aspartic acid, kainic acid and quisqualic acid, respectively, only antagonists at the former two sites are currently available. It is now reported that when applied by microiontophoresis to neurones in the rat cerebral cortex, excitatory responses to quisqualic acid can be selectively reduced by streptomycin.

Quisqualate receptors in epileptic fowl: the absence of coupling between quisqualate and N-methyl-D-aspartate receptors.

The ability of excitatory amino acid receptor agonists, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and quisqualate to produce seizures was determined in 1-2 day old epileptic and non-epileptic (carrier) chicks. Both compounds produced prolonged clonic seizures in epileptic chicks at doses which were not convulsant in carrier chicks. Seizures produced in epileptics by AMPA were suppressed by the quisqualate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), but were not prevented by pretreatment with competitive (2-amino-7-phosphonoheptanoic acid, APH) or non-competitive (MK-801) NMDA (N-methyl-D-aspartate) receptor antagonists. These data do not support the hypothesis that NMDA receptors work in concert with quisqualate receptors. Binding sites for [3H]AMPA were characterized in cerebral hemispheres of both epileptic and carrier chicks. Analysis of the data revealed no significant alterations in the binding affinity (KD) or the number of binding sites (Bmax) of AMPA to tissue preparations from epileptic chickens when compared to carriers. The latter data does not explain the increased susceptibility of epileptic fowl to the convulsant effects of quisqualate and AMPA.

Two pharmacological classes of quisqualate-induced electrical responses in rat retinal ganglion cells in vitro.

The pharmacological properties of steady state responses elicited by the excitatory amino acid agonists quisqualate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) have been examined in isolated rat retinal ganglion cells with patch electrodes. Based upon testing retinal ganglion cells with both agonists at saturating concentrations (30 microM for quisqualate and 60 microM for AMPA), these neurons can be grouped into three different categories: (a) type I cells, in which AMPA steady state responses were larger than those induced by quisqualate; (b) type II cells, in which quisqualate steady state responses were larger than or equal to those produced by AMPA; and (c) type III cells, in which neither AMPA nor quisqualate elicited responses. Regardless of cell type (I or II), AMPA responses were substantially inhibited by the antagonists kynurenate (750 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM). In contrast, the effects of these antagonists on quisqualate responses varied depending on the cell type, with both kynurenate and CNQX being more effective in type II than in type I cells. Based upon further pharmacological manipulations, it is proposed that quisqualate-induced steady state responses in retinal ganglion cells are divisible into two pharmacological classes that exist in varying proportions in these cells in vitro.

NIP-121 and cromakalim, potassium channel openers, preferentially suppress prostanoid-induced contraction of the guinea-pig isolated trachea.

We have investigated the relaxant effect of the potassium channel openers, NIP-121 and cromakalim, on spontaneous and spasmogen-induced tone in the isolated guinea-pig trachea. NIP-121 and cromakalim fully suppressed the spontaneous tone in a concentration-dependent manner and the maximal response was 89 and 97% of that to 1 mM aminophylline. The suppressant effect of NIP-121 (pD2 7.39) was 5 times stronger than that of cromakalim (pD2 6.69). Spontaneous tone was completely inhibited by the cyclooxygenase inhibitor, indomethacin, and partially inhibited by the thromboxane A2 (TXA2) antagonist, BM13177. In the presence of indomethacin, the contraction induced by prostaglandin (PG) F2 alpha and PGD2 was reversed by BM13177 to the same extent. NIP-121 and cromakalim reversed the contraction induced by PGF2 alpha, PGD2 and the TXA2 mimetic, U46619, and the effects were more potent than those observed on the contraction induced by leukotriene (LT) D4, LTC4, histamine and acetylcholine. The maximal relaxant responses (%) induced by NIP-121 and cromakalim were 97 and 96 for PGF2 alpha, 94 and 87 for PGD2, 94 and 93 for U46619, 69 and 69 for LTD4, 75 and 58 for LTC4, 73 and 61 for histamine and 1 and 16 for acetylcholine, respectively. The relaxant effect of NIP-121 on responses to these spasmogens (pD2 7.35 for PGF2 alpha, 7.40 for PGD2, 7.31 for U46619, 7.28 for LTD4, 7.09 for LTC4, and 7.15 for histamine) was about 10-20 times stronger than the effect of cromakalim (pD2 6.23 for PGF2 alpha, 6.04 for PGD2, 6.20 for U46619, 6.01 for LTD4, 5.82 for LTC4 and 5.88 for histamine).(ABSTRACT TRUNCATED AT 250 WORDS)

Peptides derived from kainic acid as antagonists of N-methyl-D-aspartate-induced neuroexcitation in rat brain.

The effects of dipeptides and an amide chemically derived from kainic acid (KA) on the response of rat striatal slices to excitatory amino acids were studied. Some of the gamma-peptides of KA were found to antagonize the response to N-methyl-D-aspartate (NMDA) more than that to quisqualate and glutamate and not to have any effect on the response to kainate. The least potent antagonists among the tested compounds were the gamma-amide of KA and the peptides of KA with beta-alanine and gamma-aminobutyric acid, whereas the gamma-kainyl peptides of the alpha-amino acids glycine, tyrosine, glutamate and KA were more active. The latter are the best blockers of the response to NMDA among the tested compounds.

The effect of D-alpha-aminoadipate on excitatory amino acid responses recorded intracellularly from motoneurones of the frog spinal cord.

The excitatory responses to amino acids were recorded intracellularly from motoneurones in the isolated frog spinal cord and the effect of the antagonist D-alpha-aminoadipate examined. An unusual profile of antagonism was obtained in that with 50-100 microM D-alpha-aminoadipate the depolarization to quisqualate was unaffected (or slightly potentiated) while those to L-glutamate, L-aspartate and N-methyl-D-aspartate were all considerably attenuated. D-alpha-aminoadipate did not influence passive membrane properties although a small hyperpolarization was sometimes evident. Dorsal root evoked excitations of motoneurones, particularly those using low strength stimulation, were also susceptible to antagonism by D-alpha-aminoadipate. These data suggest a separate neuroeffector/receptor mechanism for quisqualate compared to L-glutamate, L-aspartate and N-methyl-D-aspartate.

An intracellular analysis of amino acid induced excitations of deep dorsal horn neurones in the rat spinal cord slice.

The rat spinal cord slice preparation has been used to investigate the sensitivity of deep dorsal horn neurones to the excitatory amino acids N-methyl-D-aspartate (NMDA), quisqualate and L-glutamate. Intracellular recordings were made from 44 neurones in laminae III-VI of 14- to 16-day rats. Superfusion of quisqualate (30 microM) excited all neurones, NMDA (50 microM) excited 72% and L-glutamate (0.5-1 mM) 63% of the neurones. Depolarizations were retained after tetrodotoxin but with a reduced amplitude. The NMDA antagonist D-aminophosphonovalerate (D-APV, 10 microM) reduced NMDA and L-glutamate depolarizations by 66% and by 40%, respectively, while the quisqualate responses were enhanced by 27%. Dorsal root stimulation elicited two main patterns of activity; short-latency single/double spikes followed by subthreshold excitatory postsynaptic potentials (EPSPs) or a burst of spikes rising from a long duration composite EPSP. D-APV reduced the long-latency components of the first type and reduced the amplitude and duration of the composite EPSP of the second. These results support a specialized role for NMDA receptors in synaptic transmission in the dorsal horn.

Muscle relaxant and anticonvulsant activity of 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, a novel N-methyl-D-aspartate antagonist, in rodents.

A novel 4-substituted derivative of piperazine-2-carboxylic acid, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), with potent N-methyl-D-aspartate (NMDA) antagonist activity was evaluated as a muscle relaxant in genetically spastic rats. CPP, 0.02-0.1 mmol/kg, given intraperitoneally reduced the tonic activity in the electromyogram recorded from the gastrocnemius muscle of genetically spastic rats in a dose- and time-dependent manner. Muscle relaxation was also seen following intrathecal application of CPP, 0.0002-0.002 mumol, in genetically spastic rats. CPP, 0.1 mmol/kg, while not affecting Hoffman (H-) reflexes, depressed flexor reflexes in anesthetized rats following intravenous administration. In mice, CPP, 0.001 mumol, given intracerebroventricularly preferentially antagonized myoclonic seizures induced by NMDA and quinolinate, and had no effect on convulsions elicited by kainate, quisqualate and L-glutamate. These observations identify CPP as the most potent preferential NMDA antagonist so far tested with muscle relaxant and anticonvulsant activity resembling the profile of action of 2-amino-7-phosphonoheptanoate.