Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3-[2-[4-(2-Methylphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridine HCl (dapiprazole is a new compound endowed with a unique psychopharmacological profile. It inhibits amphetamine toxicity in grouped mice, and alcohol and morphine withdrawal syndromes, whereas it is almost inactive in the screening models for neuroleptics relying on dopaminergic activity. It also produces sedation, blocks conditioned avoidance reflex, reduces the response to noxious stimuli, has EEG synchronizing effects and inhibits the arousal reaction. Dapiprazole is a potent central and peripheral adrenolytic agent. Its acute toxicity is low. On the basis of these data, clinical investigations of dapiprazole are suggested in psychotic conditions such as the withdrawal syndromes, schizophrenia and schizo-affective disorders.
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PMID:Psychopharmacological profile of dapiprazole, a new potential antipsychotic agent. 612 97

Pharmacological effects of the novel antipsychotic, 2-(4-ethyl-1-piperazinyl)-4-(fluorophenyl)-5,6,7,8,9,10-hexahydrocycl oocta [b]pyridine (AD-5423), were compared with those of haloperidol in rats. AD-5423 suppressed hyperactivity induced by microinjecting dopamine into the nucleus accumbens (0.3-3 mg/kg p.o.), and also antagonized both apomorphine- and methamphetamine-induced decreases in firing rate of neurons in the medial prefrontal cortex (1 mg/kg i.v.), indicating antidopaminergic effects of the compound in the possible brain areas involved in pathophysiology of schizophrenia. During repeated treatment with AD-5423 (0.5 and 1 mg/kg/day p.o.), the antiavoidance effect (predictive of antipsychotic efficacy) persisted at least for 14 days, whereas tolerance developed as rapidly as within 10 days to the antagonistic effect on apomorphine-induced gnawing (predictive of acute extrapyramidal side-effects). In these tests, AD-5423 was quite similar to haloperidol in potencies and time-course patterns of the effects. However, different results were obtained between the effects of AD-5423 and haloperidol in possible animal models of tardive dyskinesia and malignant syndrome. In rats treated for 21 days with haloperidol (3 mg/kg, once a day p.o.) and (+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine [(+)SCH23390] (0.05 mg/kg, twice a day s.c.), but not with AD-5423 (10 mg/kg, once a day p.o.), 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF38393) induced a greater number of vacuous oral movements than in nontreated rats. Unlike haloperidol (3 mg/kg p.o.), AD-5423 (10 mg/kg p.o.) did not cause hyperthermia in combined treatment with veratrine (into the preoptic anterior hypothalamus).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative study of 2-(4-ethyl-1-piperazinyl)-4-(fluorophenyl)-5,6,7,8,9, 10-hexahydrocycloocta[b]pyridine (AD-5423) and haloperidol for their pharmacological activities related to antipsychotic efficacy and/or adverse side-effects. 809 63

Interactions between serotonin (5-HT) and dopamine (DA) neuronal systems in the prefrontal cortex (PFC) may be important in the pathophysiology of cognitive disorders such as schizophrenia. We have examined the effect of 5-HT, applied locally through a microdialysis probe, on extracellular DA in the PFC, and compared the response to that observed in the striatum. 5-HT in concentrations of 1 to 10 microM increased extracellular DA dose-dependently to a greater extent in the PFC than in the striatum. The PFC response was pharmacologically characterized to determine the 5-HT receptor subtype mediating the increase in DA levels. The coperfusion of selective 5-HT2A and 5-HT3 antagonists MDL 100,907 ((R-(+)-(2,3-dimethoxyphenyl)-1-[2(4-flourophenylethyl)]-4- piperidine-methanol) and MDL 72222 (3-tropanyl-3,5-dichlorobenzoate), respectively, with 5-HT failed to significantly attenuate the 5-HT induced increase of extracellular DA. Furthermore, the local application of the 5-HT2A/2C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl aminopropane did not yield an increase in extracellular DA. On the other hand, coperfusion of the selective 5-HT1B/1D antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4-carboxamide)) with 5-HT completely blocked the effect of 5-HT alone. Infusion of the selective 5-HT1B agonists CP 93,129 (3-(1,2,5,6-tetrahydro-4-pyridyl)pyrrolo[3,2-b]pyrid-5-one) and CP 94,253 (3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrolo[3,2-b]pyridine) resulted in a significant increase in extracellular DA and the effect of CP 93,129 was attenuated by coperfusion of GR 127935. The results obtained demonstrate a functional interaction between DA and 5-HT pathways in the PFC, with evidence of potential mediation by the 5-HT1B receptor subtype.
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PMID:Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization. 861 47

The dopamine D4 receptor has been implicated in the therapeutic effects of the atypical antipsychotic, clozapine. As it has been proposed that anxiolytic-like activity may contribute to the efficacy of this agent in ameliorating the negative symptoms of schizophrenia, the current study employed ethological methods to fully characterize the acute behavioural profiles of clozapine and two more selective dopamine D4 receptor antagonists, L-745,870 (3-[{4-(4-chlorophenyl)piperazin-1-yl)]methyl}-1 H-pyrrolo[2,3b]pyridine) and L-741,742 (5-(4-chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)is oxazole), in the mouse elevated plus-maze test. Results showed that while clozapine (0.3-6.0 mg/kg) dose-dependently inhibited all active behaviours (arm entries, exploration, rearing) and increased grooming and immobility, it failed to alter the major anxiety indices (percent open entries and open time). In contrast, L-745,870 (0.02-1.5 mg/kg) and L-741,742 (0.04-5.0 mg/kg) did not produce any significant behavioural changes under present test conditions. These data, which contrast markedly with the robust anxiolytic profile of the reference compound, chlordiazepoxide (10.0 mg/kg), provide little support for the suggestion that clozapine possesses anxiolytic-like properties and further indicate that selective dopamine D4 receptor antagonists are ineffective in the modulation of anxiety-related behaviours in the plus-maze.
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PMID:Dopamine D4 receptor and anxiety: behavioural profiles of clozapine, L-745,870 and L-741,742 in the mouse plus-maze. 936 63

The compound CI-1007 (R-(+)-1,2,3,6-tetrahydro-4-phenyl-1 [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine maleate) has been identified as a partial dopamine agonist and putative antipsychotic in in-vitro and in-vivo neurochemical, neurophysiological and behavioural tests. By use of microdialysis in conjunction with high-performance liquid chromatography (HPLC) with electrochemical detection, the effects of the drug on brain dopamine release, previously observed in anaesthetized animals, were shown to occur in awake animals also. Detection of peripherally administered CI-1007 in the brain, i.e. evidence of the drug's ability to penetrate the blood-brain barrier, was achieved by use of in-vivo brain microdialysis in awake, freely moving rats and capillary HPLC in combination with tandem mass spectrometry (HPLC/MS/MS). Intravenous administration of CI-1007 (40 mg kg-1) significantly inhibits dopamine release in the nucleus accumbens, a region associated with dopamine hyperactivity in schizophrenia, while having a non-significant impact on the striatal dopamine neurotransmission which is critical to regular motor function. The differential neurochemical profile of the drug indicates its potential usefulness in treating positive disease symptoms and implies that its extrapyramidal side effects are lower than those of typical antipsychotics.
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PMID:Brain extracellular levels of the putative antipsychotic CI-1007 and its effects on striatal and nucleus accumbens dopamine overflow in the awake rat. 982 62

3-([4-(4-Chlorophenyl)piperazin-1-yl]-methyl)-1H-pyrrolo-2, 3-beta-pyridine (L-745,870) is a dopamine D(4) selective antagonist that has been studied as a potential treatment for schizophrenia, with the expectation that it would not exhibit the extrapyramidal side effects often observed with the use of classical antipsychotic agents. The metabolism of L-745,870 in vivo was investigated in the rat, rhesus monkey, and human using liquid chromatography-tandem mass spectrometry and/or NMR techniques in conjunction with radiochemical detection. In all three species, two major metabolic pathways were identified, namely N-dealkylation at the substituted piperazine moiety and the formation of a novel mercapturic acid adduct. It is proposed that the latter biotransformation process involves the formation of an electrophilic imine methide intermediate, analogous to that produced from 3-methyl indole. This report appears to represent the first example of metabolic activation of a 3-alkyl-7-azaindole nucleus.
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PMID:Metabolism of A dopamine D(4)-selective antagonist in rat, monkey, and humans: formation of A novel mercapturic acid adduct. 1082 Jan 34

The dopamine D(4) receptor (D(4)R) is expressed in low density in various extrastriatal brain regions. This receptor subtype is discussed in relation to the pathophysiology and treatment of schizophrenia but no selective positron emission tomography (PET) ligand is available to date to study the distribution in vivo. The arylpiperazine derivative N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (PB-12) is a novel, high-affinity ( K(i)=0.040 nM) and selective D(4)R ligand. We radiolabeled PB-12 with carbon-11 (t(1/2) 20.4 min) by O-methylation of the corresponding desmethyl analogue N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-hydroxybenzamide (LM-190) with [(11)C]methyl triflate. Derivative LM-190 was prepared by condensing 3-hydroxybenzoic acid with the appropriate amine. For the radiolabeling, the incorporation yield was >90% and the total synthesis time including high performance liquid chromatography (HPLC) purification was about 35 min. The specific radioactivity of [(11)C]PB-12 at time of injection was 67-118 GBq x micromol(-1). PET studies in a cynomolgus monkey showed a high uptake and widespread distribution of radioactivity in the brain, including the neocortex and thalamus. About 40% of total radioactivity in plasma represented unchanged radioligand at 60 min after injection as determined by HPLC. Pretreatment with the D(4)R ligand 3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1H-pyrollo[2,3-b]pyridine (L-745,870) prior to radioligand injection failed to demonstrate receptor-specific binding in the monkey brain. Furthermore, the brain radioactivity distribution was left unaffected by pretreating with unlabeled PB-12. This failure to detect a D(4)R-specific signal may be related to a very low density of the D(4)R in primate brain, insufficient binding affinity of the radioligand, and a high background of nonspecific binding. It can be concluded from these findings that [(11)C]PB-12 is not suitable to visualize the D(4)R in the primate brain with PET.
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PMID:Carbon-11 pb-12: an attempt to visualize the dopamine d(4) receptor in the primate brain with positron emission tomography. 1115 Jul 1

Fibroblast growth factor-2 (FGF-2) is a member of a large family of trophic factors whose expression is regulated under several conditions in different areas of the brain. The goal of our experiments was to determine whether the administration of 4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-[4-(1,2,4-triazol-1-il)butyl] pyridine citrate (E-5842), a sigma-1 receptor ligand and putative atypical antipsychotic, could regulate the expression of FGF-2. After chronic treatment with E-5842 (21 days, and the animals killed 24 h after the last administration), an up-regulation was observed of the expression of FGF-2 mRNA in the prefrontal cortex and the striatum, and a down-regulation of the expression of FGF-2 mRNA in the hypothalamus of the rat brain. Acute treatment with E-5842 (one single administration and animals killed 6 h later) up-regulated FGF-2 expression in the prefrontal cortex, the striatum, the hypothalamus and the hippocampus in a dose-dependent manner. The acute up-regulation was transient and disappeared 24 h after E-5842 administration. The induction of FGF-2 in the striatum after repeated administration has been described for clozapine, but our data concerning regulation in the prefrontal cortex suggest that this effect is unique to E-5852 among other antipsychotics. Given the neuroprotective activity of FGF-2, the data presented here might be relevant to the deficit in cognition and other symptoms that appear in schizophrenia.
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PMID:Fibroblast growth factor-2 is selectively modulated in the rat brain by E-5842, a preferential sigma-1 receptor ligand and putative atypical antipsychotic. 1126 63

Use-dependent N-methyl-d-aspartate receptor (NMDAR) antagonists produce behaviors in human volunteers that resemble schizophrenia and exacerbate those behaviors in schizophrenic patients, suggesting that hypofunction of NMDAR-mediated neuronal circuitry may be involved in the etiology of clinical schizophrenia. Activation of the metabotropic glutamate receptor subtype 5 (mGluR5) enhances NMDAR-mediated currents in vitro. Thus, activation of mGluR5 could potentiate hypofunctional NMDARs in neuronal circuitry relevant to schizophrenia. To further elucidate the role of mGluR5, the present study examined the effects of mGluR5 antagonist administration, with and without coadministration of the use-dependent NMDAR antagonist phencyclidine (PCP), on locomotor activity and prepulse inhibition (PPI) of the acoustic startle response in rodents. We further examined PPI in mGluR5 knockout mice. Finally, we examined PPI after administration of the mGluR5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) alone and in combination with amphetamine. The data indicate that the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine has no effect on locomotor activity or PPI by itself but does potentiate both PCP-induced locomotor activity and disruption of PPI. We further found that mGluR5 knockout mice display consistent deficits in PPI relative to their wild-type controls. Finally, the data indicate that CHPG has no effect on PPI by itself, but ameliorates amphetamine-induced disruption of PPI. Collectively, these data suggest that mGlu5 receptors play a modulatory role on rodent PPI and locomotor behaviors and are consistent with the hypothesis that mGlu5 agonist/potentiators may represent a novel approach for antipsychotic drug development.
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PMID:Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. 1266 Mar 7

Sensorimotor gating, measured by prepulse inhibition (PPI), is a fundamental form of information processing that is deficient in schizophrenia patients and mice lacking the gene for metabotropic glutamate receptor 5 (mGluR5). Both breeding strategies and mothering behaviors are capable of influencing the behavioral phenotype of knockout (KO) mice. Previous studies found a PPI deficit and increased startle magnitudes in mGluR5 KO mice derived from homozygous matings. Here we compared the PPI of mGluR5 wildtype (WT) and KO mice derived from heterozygous matings to that seen in mice derived from homozygous matings. Possible influences of postnatal mothering behaviors were examined using two different methods of cross-fostering. The potential developmental nature of the PPI deficit of the mGluR5 KO mice was also addressed via acute administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) to C57BL/6J mice. The mGluR5 KO mice exhibited reduced PPI independently of breeding strategy or postnatal mothering behavior. Startle magnitude, however, varied with breeding strategy. The PPI deficit seen in the mGluR5 KO mice is not mimicked by acute administration of an mGluR5 antagonist, and is therefore most likely due to compensatory alterations in neuronal circuitry occurring during development independent of maternal behaviors in the postnatal environment.
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PMID:Interactions of the mGluR5 gene with breeding and maternal factors on startle and prepulse inhibition in mice. 1518 9


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