Potent NMDA Antagonist Research Articles

Is levorphanol a better option than methadone?

Methadone has been a stalwart pharmacologic option for the management of opioid drug dependence for many years. It substitutes for opioid agonists and possesses certain pharmacokinetic properties that confer characteristics preferable to those of other opioids for this application. Methadone is likewise used as an option for the treatment of pain, particularly chronic pain. It has a spectrum of pharmacodynamic activity, including contributions from non-opioid components, that translates to its specific clinical attributes as an analgesic. Unfortunately, basic science studies and accumulated clinical experience with methadone have revealed some undesirable, and even worrisome, features, including issues of safety. The benefit/risk ratio of methadone might be acceptable if there was no better alternative, but neither its pharmacokinetic nor pharmacodynamic properties are unique to methadone. We review the basic and clinical pharmacology of methadone and suggest that levorphanol should receive attention as a possible alternative. Unlike methadone, levorphanol is a more potent NMDA antagonist, possesses a higher affinity for DOR and KOR, has a shorter plasma half-life yet longer duration of action, has no CYP450 interactions or QTc prolongation risk, can be a viable option in the elderly, palliative care, and SCI patients, requires little to no need for co-administration of adjuvant analgesics, and has potentially a lower risk of drug-related Emergency Department visits compared to other opioids.

Low-level lead exposure triggers neuronal apoptosis in the developing mouse brain

While the toxic effects of lead have been recognized for millennia, it has remained a significant public health concern due to its continued use and toxicological potential. Of particular interest is the increased susceptibility of young children to the toxic effects of lead. Although the exact mechanism(s) for lead toxicity is currently not well understood, research has established that it can be a potent NMDA antagonist. Previous research has established that exposure to NMDA antagonists during the brain growth spurt period (first 2weeks of life in mice) can produce apoptotic neurodegeneration throughout the brain. Based on this information, the ability of lead exposure (two injections of 350mg/kg lead 4h apart) to produce apoptosis in the neonatal mouse brain was assessed histologically 8–24h after treatment using activated caspase-3 immunohistochemistry, De Olmos silver technique, Nissl staining, and electron microscopy. Lead exposure produced significant neurodegeneration in the caudate/putamen, hippocampus, subiculum, and superficial and deep cortical layers of the frontal cortical regions. Further ultrastructural examination revealed cellular profiles consistent with apoptotic cell death. Statistical results showed that lead exposure significantly increased apoptotic neurodegeneration above that seen in normal controls in animals treated at postnatal day 7, but not on day 14. The results of this study may provide a basis for further elucidation of mechanisms through which the immature nervous system may be particularly susceptible to lead exposure.

Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists

A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having ( S)-configuration at the 2-position of the piperidine ring and 4-position of the dioxolane ring were considered. Key steps in the synthesis were an imino-Diels–Alder reaction of enantiomerically pure imine ( S)- 13, which had been obtained from d-mannitol, with Danishefsky’s Diene 14 and the replacement of the p-methoxybenzyl protective group with a Cbz-group. It was shown that ( S, S)-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4-substituent ((4 S)-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety (( S, S, S)- 5, K i = 28 nM), a fluorine atom (( S, S, S)- 6, WMS-2539, K i = 7 nM) and two fluorine atoms (( S, S)- 7, K i = 48 nM) in position 4 represent the most potent NMDA antagonists with high selectivity against σ 1 and σ 2 receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity.

ChemInform Abstract: Asymmetric Synthesis of a Potent and Selective Competitive NMDA Antagonist.

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Synthesis and NMDA receptor affinity of dexoxadrol analogues with modifications in position 4 of the piperidine ring

A series of dexoxadrol (3) analogues with various substituents at position 4 of the piperidine ring has been synthesized and pharmacologically evaluated. Key steps in the synthesis are a hetero-Diels–Alder reaction of the dioxolane-derived imine 10 with Danishefsky's diene 11 and replacement of the p-methoxybenzyl protective group by a Cbz group. All possible diastereomers were synthesized, respectively. It was shown that like-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4 substituent are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidine with a hydroxy moiety at position 4 (17d, WMS-2508, Ki = 44 nM) represents the most potent NMDA antagonist with high selectivity against σ1 and σ2 receptors, and the polyamine binding site of the NMDA receptor. The high sensitivity of the receptor ligand interaction became evident since methyl ethers with unlike-configuration of the ring junction (19a, 19b) prefer the σ1 receptor with high selectivity.

Early and effective use of ketamine for treatment of phantom limb pain

Treatment for phantom limb pain is difficult and challenging. There is often suboptimum treatment with fewer than 10% receiving lasting relief. Treatments based broadly on other neuropathic pains may not be appropriate for a clinical success. We report a case of phantom limb pain, which proved resistant to multiple analgesics, including opioids and continuous epidural blockade. Treatment with intravenous (IV) ketamine as an alternate day infusion, gave complete remission of phantom limb pain. This demonstrates an early and effective use of a potent NMDA antagonist for treatment of phantom limb pain. Mechanisms underlying phantom limb pain are briefly discussed.

Ketamine pretreatment with venous occlusion attenuates pain on injection with propofol

Ketamine pretreatment with venous occlusion attenuates pain on injection with propofol

N1-Dansyl-spermine: a potent polyamine antagonist

The potential polyamine antagonist action of N 1-dansyl-spermine (a potent NMDA antagonist) was assessed in two in vivo mouse models of polyamine action. Co-administration of N 1-dansyl-spermine (2–10 μg, i.c.v.) with spermine (100 μg, i.c.v.) resulted in a dose-dependent antagonism of the spermine-induced CNS excitation (body tremor and fatal tonic convulsions). In addition, the same dose of N 1-dansyl-spermine antagonised spermine's enhancement of NMDA-induced convulsions. These results suggest that N 1-dansyl-spermine is in vivo a potent antagonist of the CNS effects of spermine and of its action at the positive polyamine modulatory site on the NMDA receptor.

Evolution of the Management and Prevention of Childhood Lead Poisoning: Dependence of Advances in Public Health on Technological Advances in the Determination of Lead and Related Biochemical Indicators of Its Toxicity

While the toxic effects of lead have been recognized for millennia, it has remained a significant public health concern due to its continued use and toxicological potential. Of particular interest is the increased susceptibility of young children to the toxic effects of lead. Although the exact mechanism(s) for lead toxicity is currently not well understood, research has established that it can be a potent NMDA antagonist. Previous research has established that exposure to NMDA antagonists during the brain growth spurt period (first 2 weeks of life in mice) can produce apoptotic neurodegeneration throughout the brain. Based on this information, the ability of lead exposure (two injections of 350 mg/kg lead 4 h apart) to produce apoptosis in the neonatal mouse brain was assessed histologically 8–24 h after treatment using activated caspase-3 immunohistochemistry, De Olmos silver technique, Nissl staining, and electron microscopy. Lead exposure produced significant neurodegeneration in the caudate/putamen, hippocampus, subiculum, and superficial and deep cortical layers of the frontal cortical regions. Further ultrastructural examination revealed cellular profiles consistent with apoptotic cell death. Statistical results showed that lead exposure significantly increased apoptotic neurodegeneration above that seen in normal controls in animals treated at postnatal day 7, but not on day 14. The results of this study may provide a basis for further elucidation of mechanisms through which the immature nervous system may be particularly susceptible to lead exposure.

The use of ligand binding in assays of NMDA receptor function.

AbstractThe quantification of drug interaction with NMDA receptors has been greatly facilitated by the use of ligand binding assays. The first assays for this receptor measured NMDA-sensitive [3H]glutamate binding (see 1 for review). However, [3H]glutamate has relatively low affinity for the receptor, and is also a substrate for transport processes in brain membranes, which can make it difficult to isolate receptor binding from ligand sequestration. The recognition that dissociative anesthetics, such as phencyclidine and ketamine, were NMDA receptor antagonists (2,3) was an important pharmacological advance, because these drugs were more potent NMDA antagonists that others available at the time. However, phencyclidine also proved to be a difficult ligand to use because of nonspecific binding. The identification of MK801 (dizocilpine) and thienylphencyclidine (TCP) as highly potent and very selective inhibitors of NMDA receptor function (4–6) brought the possibility of ligand binding to NMDA receptors into the mainstream.KeywordsNMDA ReceptorLigand Binding AssayGlycine SiteNMDA Receptor FunctionFilter StripThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

N-Phosphonoalkyl-5-aminomethylquinoxaline-2,3-diones: In vivo active AMPA and NMDA(glycine) antagonists

N-Substituted 5-aminomethylquinoxalinediones containing carboxy or phosphonic acids yield potent and selective AMPA and/or NMDA (glycine-binding site) antagonists. Phosphonic acid derivatives are particularly water-soluble and display potent anticonvulsant effects in the electroshock-induced convulsion assay in mice.

Design and synthesis of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere.

The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.

Glutamate antagonists and Parkinson's disease: A review of clinical data

Several lines of evidence demonstrate that glutamate antagonists can reverse experimental parkinsonism in animals. However, few clinical studies have been undertaken, principally because there is a shortage of glutamate antagonists which are considered safe for human use. This paper details the results of preliminary studies carried out on dextromethorphan, an anti-tussive agent and a weak open-channel blocker of the NMDA receptor; and the cerebral anti-ischaemic drug ifenprodil, a novel non-competitive inhibitor of the polyamine modulatory site on the NMDA receptor. Trials with these two compounds in small groups of parkinsonian volunteers have not demonstrated conclusive symptomatic improvement. These results do not exclude a possible role for NMDA receptor antagonists in the pharmacotherapy of Parkinson's disease, but rather point to the need for developing more potent and safe NMDA antagonists, with better pharmacodynamic and pharmacokinetic profiles.

Homocysteate‐Evoked Release of Acetylcholine from the Rabbit Retina

The cholinergic amacrine cells of the rabbit retina can be labeled with [3H]choline and the activity of the cholinergic population monitored by following the release of [3H]acetylcholine. It has been proposed that L-homocysteate may be the main endogenous transmitter released onto cholinergic amacrine cells by bipolar cells. Therefore, we have examined the effects of the isomers of homocysteate on the release of [3H]acetylcholine. In magnesium-free medium, D-homocysteate was slightly more potent than the L-isomer. The addition of magnesium, which blocks responses mediated by NMDA receptors, preferentially reduced but did not eliminate, the response to L-homocysteate. 2-Amino-7-phosphonoheptanoate, a potent NMDA antagonist, preferentially blocked L-homocysteate evoked responses. 6,7-Dinitroquinoxaline-2,3-dione, a potent kainate antagonist, preferentially blocked D-homocysteate-evoked responses. Therefore, in the rabbit retina, L-homocysteate is an NMDA-preferring agonist, whereas D-homocysteate is a kainate-preferring agonist. In addition, we found that L-homocysteate can activate the physiologically activated kainate receptor but only when used in millimolar concentrations and under conditions that minimize NMDA-receptor activation. However, the low potency of L-homocysteate combined with low affinity for the glutamate transporter, lack of immunocytochemical localization in bipolar cells, and low retinal content place serious limitations on the role of L-homocysteate at the bipolar-to-cholinergic amacrine cell synapse.

Intrahippocampal administration of (+)-SKF 10,047, a σ ligand, reverses MK-801-induced impairment of working memory in rats

In order to clarify the roles of the hippocampal σ site and phencyclidine (PCP) binding site on the NMDA receptor/channel complex in the regulation of working memory in rats, the effects of intrahippocampal administration of ligands for both binding sites on this behavior were examined with a three-panel runway task. MK-801, a potent noncompetitive NMDA antagonist with high affinity for the PCP site, significantly increased the number of working memory errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), when injected bilaterally at 0.1 and 0.18 μg/side into the dorsal hippocampus. However, intrahippocampal injection of (+)-SKF 10,047, a σ ligand, at doses up to 1.0 μg/side had no significant effect on the number of working memory errors. The working memory impairment induced by intrahippocampal MK-801 (0.18 μg/side) was attenuated by concurrent injection of 1.0 μg/side (+)-SKF 10,047, but not by that of 1.0 μg/side (−)-SKF 10,047. These results suggest that activation of hippocampal σ and PCP binding sites exerts antagonistic effects on working memory function, possibly through modulation of NMDA receptor-mediated glutamatergic neurotransmission.

Delayed treatment with AMPA, but not NMDA, antagonists reduces neocortical infarction.

We tested the abilities of two potent non-N-methyl-D-aspartate (non-NMDA) glutamate antagonists [2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX)] and [1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazep ine hydrochloride (GYKI 52466)] to reduce neocortical infarction following 2 h of transient middle cerebral artery occlusion in a hypertensive stroke model in the rat and compared these effects against, and in combination with, a potent NMDA antagonist [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-amine maleate (MK-801)]. In Expt. 1, an already established cytoprotective dose of Na(+)-NBQX (30 mg/kg i.p. x 3) was compared with saline (1 ml), the NMDA antagonist MK-801 (1 mg/kg i.p. x 3), and a combination of the same doses of both NBQX and MK-801. Initial doses were delayed to 90 min following occlusion with subsequent injections at the time of reperfusion and 30 min following reperfusion. Saline-treated rats sustained 181 +/- 32 mm3 (n = 15) of neocortical infarction (mean +/- SD). This was significantly reduced by NBQX to 137 +/- 25 mm3 (n = 15, p < 0.05) of damage. Neither MK-801 (170 +/- 33 mm3; n = 11) nor the combination of MK-801 and NBQX (169 +/- 20 mm3; n = 6) proved to be cytoprotective when given with a 90-min delay. In Expt. 2, NBQX (30 mg/kg) was dissolved (6 mg/ml) in 5% dextrose and compared with both saline and dextrose (1.2 ml) i.v. infusions given over a 4-h period starting 1 h after occlusion. Saline-treated rats had a mean infarct of 183 +/- 27 mm3 (n = 6), dextrose-treated had 200 +/- 30 mm3 (n = 9), while for NBQX-treated rats it was reduced to 129 +/- 60 mm3 (n = 10, p < 0.05). Intravenous NBQX precipitated into the renal tubules, causing nephrotoxicity. In Expt. 3, rats were given either saline (1 ml i.p.) or GYKI 52466 (10 mg/kg i.p.) at 30 and 90 min following occlusion and at 30, 90, and 150 min following reperfusion. Saline-treated rats sustained 187 +/- 27 mm3 of neocortical infarction (n = 7), while those treated with GYKI 52466 were protected, with 139 +/- 38 mm3 of infarction (n = 7, p < 0.05). A clinically useful role for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate antagonists in embolic stroke is envisaged if nontoxic drugs can be developed, since cerebroprotection was achieved with delayed treatment with both of these lead compounds.

Asymmetric synthesis of a potent and selective competitive NMDA antagonist

(2R,4R,5S)-2-Amino-4,5-(1,2-cyclohexyl)-1-phosphonoheptanoic acid (15) has been prepared by an efficient nine-step route (16% overall yield) which uses chemoenzymatic processess to establish all absolute stereochemistry. This compound was found to be the most active isomer of the previously reported isomeric mixture, NPC 12626. In addition, synthetic routes were developed for the stereochemically unambiguous preparation of all the other cis isomers of this racemate. All of the synthetic pathways utilized enzymatic hydrolysis of a meso diester to prepare key optically pure building blocks. Pharmacological evaluation of the isomers indicates that 15 is one of the moat potent and least toxic NMDA antagonists discovered to date

Enzymatic asymmetric synthesis of (2R, 4R, 5S)-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid, a potent, selective and competitive NMDA antagonist

The title compound was prepared by an efficient route which used chemoenzymatic processes to establish all absolute stereochemistry. This compound was shown to be the active isomer of the previously reported isomeric mixture, NPC 12626.

Effects of NMDA receptor antagonists in squirrel monkeys trained to discriminate the competitive NMDA receptor antagonist NPC 12626 from saline

Because excitatory amino acids have been implicated in several physiological phenomena, antagonists of excitatory amino acid function may have significant therapeutic potential as anticonvulsant, neuroprotectants and anxiolytics. Drug discrimination procedures in animals have proven useful to compare and contrast the behavioral effects of site-selective NMDA antagonists. In the only previous study using a competitive NMDA antagonist as a training drug, rat wwere trained to discriminate NPC 12626 (2-amino-4,5(1,2-cyclohexyl)-7-phosphonoheptanoic acid) from nondrug. The major goal of the present study was to establish and characterize a nonhuman primate model of NPC 12626 discrimination. Adult male squirrel monkeys were trained to discriminate NPC 12626 from saline under a two-lever fixed ratio-30 schedule of food reinforcement. The monkeys required between 80 and 120 training sessions to acquire this discrimination after the training dose had been raised from 3 to 20 mg/kg i.m. The competitive NMDA antagonists CGP 37849 (D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid) and CPPene (D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid) substituted completely for NPC 12626, while the potent noncompetitive NMDA antagonist, dizocilpine (MK-801), did not. These results reflect a profile of discriminative stimulus effects which support that observed in rats and establish a primate model for use in further study of the behavioral effects of the competitive NMDA antagonists.

Blockade of mu and kappa 1 opioid analgesic tolerance by NPC17742, a novel NMDA antagonist

NPC17742 is a potent competitive NMDA antagonist. Low doses of NPC17742 prevent the development of tolerance to repeated daily injections of the mu agonist morphine and the kappa 1 agonist U50,488H. However, NPC17742 at these same doses is without effect against the kappa 3 analgesic naloxone benzoylhydrazone (NalBzoH). At these doses, NPC17742 does not significantly influence morphine's ED 50 value following single or repeated doses of the NMDA antagonist. The ability of NPC17742 to block tolerance to U50488H distinguishes this compound from other NMDA antagonists and raises the possibility of subclasses of NMDA antagonists. Furthermore, these results emphasize the different mechanisms involved with analgesic tolerance among mu, kappa 1 and kappa 3 receptors.