GV196771A, an NMDA receptor/glycine site antagonist, attenuates mechanical allodynia in neuropathic rats and reduces tolerance induced by morphine in mice

Quartaroli, M.; Fasdelli, Nicola; Bettelini, L.; Maraia, G.; Corsi, Mauro

doi:10.1016/s0014-2999(01)01278-x

Cited by 37 publications

(13 citation statements)

References 37 publications

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“…‫,ء‬ p Ͻ 0.05; ‫,ءء‬ p Ͻ 0.01 versus vehicle-treated animals (one-way ANOVA followed by Dunnett's t test). ance, as reported for other NMDA antagonists (Quartaroli et al, 2001), remains to be determined.…”

Section: Discussionmentioning

confidence: 75%

Antinociceptive Activity of the N-Methyl-d-aspartate Receptor Antagonist N-(2-Indanyl)-glycinamide Hydrochloride (CHF3381) in Experimental Models of Inflammatory and Neuropathic Pain

Villetti¹,

Bergamaschi²,

Bassani³

et al. 2003

J Pharmacol Exp Ther

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N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) is a novel low-affinity, noncompetitive N-methyl-D-aspartate receptor antagonist. The current study compared the antinociceptive effects of CHF3381 with those of gabapentin and memantine in in vitro and in vivo models of pain. In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon. CHF3381 suppressed the maintenance of carrageenan-induced thermal and mechanical hyperalgesia in the rat with a minimum significantly effective dose (MED) of 30 mg/kg p.o. Memantine produced a partial reversal of both thermal and mechanical hyperalgesia (MED ϭ 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED ϭ 10 mg/kg s.c.), but did not affect thermal hyperalgesia. In the mouse formalin test, CHF3381 and memantine preferentially inhibited the late phase (MED ϭ 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED ϭ 30 mg/kg s.c.). Unlike morphine, CHF3381 chronic administration was not accompanied by the development of tolerance in the formalin test. Furthermore, morphine tolerance did not cross-generalize to CHF3381. In rats with a sciatic nerve injury, CHF3381 relieved both cold and mechanical allodynia (MED ϭ 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED ϭ 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED ϭ 50 mg/kg p.o.). Memantine (15 mg/kg i.p.) produced an antinociceptive effect, whereas gabapentin (100 mg/kg p.o.) had no significant effect. Thus, CHF3381 may be useful for the therapy of peripheral painful neuropathies.

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Section: Discussionmentioning

confidence: 75%

Antinociceptive Activity of the N-Methyl-d-aspartate Receptor Antagonist N-(2-Indanyl)-glycinamide Hydrochloride (CHF3381) in Experimental Models of Inflammatory and Neuropathic Pain

Villetti¹,

Bergamaschi²,

Bassani³

et al. 2003

J Pharmacol Exp Ther

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“…The authors suggest that these compounds may block nociceptive signals in the thalamus [103]. GV196771A has also been reported to reduce the morphine tolerance in early phase and late phase formalin [198].…”

Section: Competitive Glycine Site Antagonistsmentioning

confidence: 97%

N-Methyl-D-Aspartate Receptor (NMDA) Antagonists as Potential Pain Therapeutics

Brown¹,

Krupp²

2006

CTMC

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NMDA receptors are known to be involved in nociceptive transmission and pain processing. Many structurally diverse NMDA antagonists have been reported to have activity in both animal models and clinical models of neuropathic pain. Untoward side effects such as ataxia and sedation have severely limited the clinical uses of this class of potential therapeutics. However, antagonists at the glycine-site, NR2B sites and weak-binding channel blockers have demonstrated an improved side effect profile in animal models of pain. These types of compounds may hold potential promise for future pain therapies. This review covers reported pain data surrounding representative examples of NMDA antagonists and provides a current assessment of potential clinical utility.

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“…Preliminary problems with glycine site antagonists included poor systemic availability has now been overcome with agents like GV196771A ((E)-4,6-Dichloro-3-(2-oxo-1-phenylpyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid sodium salt) or SM-31900 (3(S)-(2-(4-(Amino methyl) -2-(1(R)-carboxyethoxy)phenylamino) -2-oxoethyl) -7-chloro -1,3,4,5-tetrahydrobenzo(c,d)indole -2-carboxylic acid hydrochloride) which are not only of very high affinity, but also have improved pharmacokinetic and physicochemical properties, such as good brain permeation and solubility [94]. Although these compounds were not tested in animal models related to alcoholism, the facts that SM-31900 has a potent anticonvulsant activity [97], GV196771A can inhibit the development of morphine tolerance [174] and both compounds are devoid of behavioural side effects (hyperactivity, motor dysfunction) make these compounds promising candidates also for the treatment of alcoholism.…”

Section: Glycine-b Site Nmdar Antagonistsmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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GV196771A, an NMDA receptor/glycine site antagonist, attenuates mechanical allodynia in neuropathic rats and reduces tolerance induced by morphine in mice

Cited by 37 publications

References 37 publications

Antinociceptive Activity of the N-Methyl-d-aspartate Receptor Antagonist N-(2-Indanyl)-glycinamide Hydrochloride (CHF3381) in Experimental Models of Inflammatory and Neuropathic Pain

Antinociceptive Activity of the N-Methyl-d-aspartate Receptor Antagonist N-(2-Indanyl)-glycinamide Hydrochloride (CHF3381) in Experimental Models of Inflammatory and Neuropathic Pain

N-Methyl-D-Aspartate Receptor (NMDA) Antagonists as Potential Pain Therapeutics

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

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