Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The various clinical effects of benzodiazepines have been attributed to the presence of saturable binding sites, stereospecific and of high affinity in the central nervous system. Good correlations have been described between the inhibition of the binding of [3H]diazepam and the anticonvulsant and anticonflictual properties of benzodiazepines. Such results would suggest that these binding sites are the pharmacological receptors responsible for the therapeutic properties of benzodiazepines. In addition, the neuromediator which has been associated with benzodiazepines in terms of its functions is GABA. Up to the present, the anticonvulsant and anticonflictual properties of substances acting on benzodiazepine receptors could not apparently be dissociated. However, b using quinoline derivatives we have been able to dissociate anticonflictual and anticonvulsant properties for substances acting upon benzodiazepine receptors. These substances (PK 8165 and PK 9084) displace diazepam from binding sites (Ki of 100 to 400 nM) in the brain but not peripherally. The fact that PK 9084 and PK 8165 are more active on benzodiazepine derivatives in the presence of anions suggests that they act upon receptors coupled with a chloride ionophore-like. Benzodiazepines, PK 8165 and PK 9084 have anticonflictual properties but cause neither ataxia nor sedation even at doses 5 to 20 times greater than anticonflictual doses. Furthermore, these compounds are not anticonvulsant. In contrast to benzodiazepines, PK 8165 and PK 9084 do not decrease the cGMP of the Purkinje cells of the cerebellum. This cGMP pool being the reflection of the activation of GABAergic receptors, it would seem that these substances must act on a sub-unit of benzodiazepine receptors not coupled with GABA but associated with the chloride ionophore. This sub-unit could be responsible for the anticonflictual properties of substances acting upon benzodiazepine receptors.
 ...
PMID:[Anxiety receptors: new pharmacological approach (author's transl)]. 612 75

The glycine B receptor partial agonists L 687,414, D-cycloserine and (+)-HA 966, and the glycine B receptor antagonists MDL 29,951 and 5,7-dichloro-2,4 dihydroxy-3-phenyl-quinoline dione (DCPQ) dose-dependently inhibited the late phase (LP) of formalin-induced licking (FIL) elicited by intraplantar formalin in mice at doses exerting little motor disruption in the rotarod test. In distinction, the early phase (EP) of FIL and the writhing response to intra-abdominal acetic acid were little influenced and, irrespective of stimulus intensity, they failed to modify the tail-flick response to phasic, thermal or mechanical stimulation of the tail. In contrast to glycine B ligands, competitive antagonists at the NMDA receptor recognition site (CPP, CGS 19755, CGP 34879 and 39551) and blockers of the associated ion channel ((+)-MK 801, (-)-MK 801, memantine and ketamine) all blocked both the LP and EP of FIL and induced ataxia at comparable doses. In conclusion, normalization of transmission at NMDA receptors by inhibition of the coupled glycine B site preferentially elicits antinociception against prolonged (chemical) noxious stimulation in the absence of a marked influence upon motor coordination.
 ...
PMID:Chemically-diverse ligands at the glycine B site coupled to N-methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin-induced pain in mice. 781 23

In the present work we evaluated the anticonvulsant effects of two novel antagonists of the glycine co-agonist site (glycineB receptor) within the N-methyl-D-aspartate (NMDA) receptor complex, MRZ 2/576 (a tricyclic pyrido-phtalazin dione derivative) and L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)quinoline). As a model of epilepsy we used amygdala-kindled rats, which are considered as a model to study the efficacy of drugs against human complex partial seizures. MRZ 2/576 (2.5-10 mg/kg i.p. 15 min before testing) did not influence afterdischarge threshold, which is believed to be the most subtle indicator of efficacy against kindled seizures, nor did it affect other measures of seizure activity such as seizure severity, seizure duration and afterdischarge duration. However, MRZ 2/576 produced dose-dependent ataxia as measured in the open field and rotarod test. The highest dose tested (10 mg/kg) also markedly reduced rectal temperature (by about 1.5 degrees C). L-701,324 (2.5-10 mg/kg i.p. 30 min before testing) dose dependently and significantly increased afterdischarge threshold, but other seizure parameters remained unchanged. The ataxia produced by lower doses of L-701,324 (2.5 and 5 mg/kg) was more pronounced than that caused by MRZ 2/576. However, the ataxia observed following the higher dose of L-701,324 (10 mg/kg) was less intense than that elicited by MRZ 2/576. The behavioral alterations produced by the two drugs did not resemble those characteristic for classical competitive and uncompetitive NMDA receptor antagonists. In conclusion, our data indicate that glycineB receptor antagonists are not promising candidates for the treatment of complex partial seizures in humans, at least as monotherapy.
 ...
PMID:Weak anticonvulsant effects of two novel glycineB receptor antagonists in the amygdala-kindling model in rats. 954 90

The aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non-NMDA receptors offers advantages for treatment of epileptic seizures compared to drugs which antagonize only one of these ionotropic glutamate receptors. The novel glutamate receptor antagonist LU 73068 (4,5-dihydro-1-methyl-4-oxo-7-trifluoromethylimidazo[1,2a]quinoxal ine-2-carbonic acid) binds with high affinity to both the glycine site of the NMDA receptor (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). In comparison, the prototype non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline) binds with high affinity to AMPA receptors only. Both NBQX and LU 73068 were about equieffective after i.p. injection in mice to block lethal convulsions induced by AMPA or NMDA. In the rat amygdala kindling model of temporal lobe epilepsy, LU 73068 dose-dependently increased the focal seizure threshold (afterdischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizures with an ED50 of 4.9 mg kg(-1). Up to 20 mg kg(-1), only moderate adverse effects, e.g. slight ataxia, were observed. NBQX, 10 mg kg(-1), and the glycine/NMDA site antagonist L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-quinoline-2(1H)one), 2.5 or 5 mg kg(-1), exerted no anticonvulsant effects in kindled rats when administered alone, but combined treatment with both drugs resulted in a significant ADT increase. The data indicate that combination of glycine/NMDA and non-NMDA receptor antagonism in a single drug is an effective means of developing a potent and effective anticonvulsant agent.
 ...
PMID:LU 73068, a new non-NMDA and glycine/NMDA receptor antagonist: pharmacological characterization and comparison with NBQX and L-701,324 in the kindling model of epilepsy. 986 55