NMDA antagonists noncompetitive

Opioids also interact with excitatory amino acid neurotransmitters. At lower micromolar concentrations, p agonists (e.g., DAMGO) enhance NMDA activity in the nucleus accumbens, but inhibit non-NMDA activity (Martin et al. 1997). At higher concentrations (5 pM), NMDA currents are reduced. Conversely, central administration of glutamate can precipitate a withdrawal syndrome in morphine-dependent animals, similar to the opioid antagonist naloxone. NMDA mechanisms also appear to be involved in the development of morphine tolerance. Competitive and noncompetitive NMDA antagonists and inhibitors of nitric oxide synthase reduce or eliminate tolerance to morphine (Elliott et al. 1995 Bilsky et al. 1996). However, this does not occur for tolerance to k opioids. Pharmacokinetics... 

Motor effects Harmaline produces a motor tremor (8-14 Hz) through activation of cells in the inferior olive, which is blocked by noncompetitive NMDA antagonists (Du et al. 1997 Stanford and Fowler 1998). Harmaline tremor is also reversed by benzodiazepine agonists (Robertson 1980). The tremor is initiated by synchronous rhythms in the olivocere-bellar system and red nucleus (Lorden et al. 1988 Gogolak et al. 1977 Batini et al. 1980). The tremor is associated with increased cGMP in the cerebellum, and tolerance with a relative normalization of cGMP (Lutes et al. 1988). Rapid tolerance develops to this effect with repeated doses. 

Glutamate systems have long been implicated in the pathophysiology of schizophrenia. Strong if circumstantial evidence comes from the psychosis associated with phencyclidine (PGP) administration PGP blocks of the ion channel the glutamate/NMDA receptor. Psychosis due to PGP and other noncompetitive NMDA antagonists includes the development of negative as well as positive symptoms and therefore is considered a better model of schizophre-... 

The noncompetitive antagonists of glutamate include phencyclidine, ketamine, N-allylnormetazocine, dextromethorphan, and dyzolcipine. The action of these compounds depends on the previous opening situation of the channel. Unfortunately, some of these useful NMDA antagonists have a narrow therapeutic margin. This could explain the contradictory results of studies. 

Ebert, B., Andersen, S Krogsgaard-Larsen, P. Ketobemidone, methadone, and pethidine are noncompetitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord, Neurosci. Lett. 1995, 187, 165-168. 

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, et al. 1994. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51 199-214. 

One of the most popular hypotheses to explain schizophrenia, the glutamate hypothesis of schizophrenia, is based on the observation of psychotomimetic effects of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), dizocilpine (MK-801), and ketamine. Like amphetamine, NMDA antagonists produce a psychosis-like state when administered to healthy individuals. Further... 

The quadracyclic ( )-5-aminocarbonyl-10,ll-dihydro-5H-dibenzo[a,c ]cyclohepten-5,10-imine (ADCI,47), results from the fusion of two active anticonvulsant compounds, MK 801 (dizocilpine,46), a potent noncompetitive NMDA antagonist (224, 225) and carbamazepine (2). The compound acts as a selective, low affinity channel blocker of the NMDA receptor and also possesses Na" channel-blocking activity (226). ADCI is devoid of the tendency to cause behavioral impairment as MK 801. ADCI is a racemate, although the (- -)-enantiomer displays a four- to fivefold greater potency at the NMDA receptor and a greater than twofold potency for seizure models in animals. There was no enantioselectivity in the Na" channel evaluation, however. The (- -)-enantiomer (SGB-017)is currently in Phase II of clinical development. 

The hypoglutamatergic hypothesis of schizophrenia is attractive because it is consistent with the lack of changes in Da number in schizophrenia, and the increases in dopamine release in schizophrenia. They are also consistent with the ability of the noncompetitive NMDA antagonists PCP and ketamine to induce behaviors reminiscent of the positive symptoms of schizophrenia in normals and precipitate these episodes in patients. Ketamine was administered to schizophrenic patients acutely in a blinded, placebo-controlled trial (31). The drug caused a dose-related initiation of positive psychotic symptoms that were not blocked by haloperidol. The patients... 

Hyperlocomotion and stereotyped behaviors induced in rodents by noncompetitive NMDA antagonists such as PCP and dizo-cilpine are antagonized by a wide range of antipsychotics (116, 117, 129-133). PCP can model in rats the negative symptomatology of social interaction (119, 134, 135). Chronic... 

The noncompetitive NMDA antagonist ion channel blockers such as PCP (148) and the competitive antagonists such as CGS 19755 (149) are both psychotomimetic in humans... 

Con-G is a selective competitive antagonist for the NMDA NRB2 site and displays an improved therapeutic ratio when compared to noncompetitive NMDA antagonists such as MK-801. The residue at position 5 of the peptide sequence is thought to play a particularly important role in the subunit specificity of the toxin. Con-T has been shown to inhibit both the NR2A and NR2B subunits of the NMDA receptor. Spinal delivery of both Con-G and Con-T produces antinociceptive effects at doses 10 times lower than those associated with motor impairment and 20 times lower than those associated with side effects in models of injury-invoked pain. ... 

It has been reported that multiple doses of a non-NMDA agonist (GYKI 52466) resulted in a substantially greater loss of Purkinje cells and microglial activation compared to ibogaine (50-100 mg/kg) alone (158). On the other hand, the noncompetitive NMDA antagonist MK-801 (1 mg/kg) markedly... 

Ketamine is one of the most widely known and medically used NMDA receptor antagonists (NMDAR) and memantine is similar in that it is a noncompetitive NMDA antagonist but is better tolerated in patients because of multiple theorized properties including the ability to bind only (or preferentially) to open channels the tendency to inhibit faster, or with higher affinity, at higher agonist concentration a relatively low affinity of inhibition being an open channel blocker with a fast off-rate compared with ketamine [1,2]. 

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