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

The in vitro and in vivo pharmacology of two glycine transporter-1 (GlyT1) inhibitors, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine (NFPS) and R,S-(+/-)N-methyl-N-[(4-trifluoromethyl)phenoxy]-3-phenyl-propylglycine (Org 24461), was studied. NFPS and Org 24461 inhibited the uptake of [3H]glycine in hippocampal synaptosomal preparation with IC(50) values of 0.022 and 2.5 microM. Neither NFPS nor Org 24461 (0.1 microM) showed significant binding to alpha-1, alpha-2, and beta-adrenoceptors, D(1) and D(2) dopamine receptors, and 5-HT(1A) and 5-HT(2A) serotonin receptors in membranes prepared from rat brain or to cloned 5-HT(6) and 5-HT(7) receptors. At 10 microM concentrations, binding affinity was measured for NFPS to 5-HT(2A) and 5-HT(2C) serotonin receptors and alpha-2 adrenoceptors and for NFPS and Org 24461 to 5-HT(7) serotonin receptors. Glycine (0.1 mM) and sarcosine (5 mM) increased [3H]glycine efflux from superfused rat hippocampal slices preloaded with [3H]glycine. NFPS and Org 24461 (0.1 mM) did not influence [3H]glycine efflux, however, they inhibited glycine-induced [3H]glycine release. These findings indicate that NFPS and Org 24461 selectively inhibit glycine uptake without being substrates of the transporter protein. Several antipsychotic tests were used to characterize antipsychotic effects of NFPS and Org 24461 in vivo. These compounds did not alter apomorphine-induced climbing and stereotypy in a dose of 10 mg/kg p.o. in mice and did not induce catalepsy in a dose of 10 mg/kg i.p. in rats. The ID(50) values of NFPS were 21.4 mg/kg and higher than 30 mg/kg i.p. for inhibition of phencyclidine (PCP)- and D-amphetamine-induced hypermotility in mice and these values were 2.5 and 8.6 mg/kg i.p. for Org 24461. NFPS and Org 24461 did not exhibit anxiolytic effects in light-dark test in mice, in the meta-chlorophenylpiperazine (mCPP)-induced anxiety test (minimal effective dose or MED was higher than 3 mg/kg i.p.) and in the Vogel conflict drinking test in rats (MED was higher than 10 mg/kg i.p.). Both NFPS and Org 24461 (1-10 mg/kg i.p.) reversed PCP-induced changes in EEG power spectra in conscious rats. These data support the view that GlyT1 inhibitors may have potential importance in treatment of negative symptoms of schizophrenia.
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PMID:The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study. 1266 95

Dopamine constitutes about 80% of the content of central catecholamines and has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to report the structural design of two N-phenylpiperazine derivatives, compound 4: 1-[1-(4-chlorophenyl)-1H-4-pyrazolylmethyl]-4-phenylhexahydropyrazine and compound 5: 1-[1-(4-chlorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-4-phenylhexahydropyrazine, planned to be dopamine ligands, and their dopaminergic action profile. The two compounds were assayed (dose range of 15-40 mg/kg) in three experimental models: 1) blockade of amphetamine (30 mg/kg, ip)-induced stereotypy in rats; 2) the catalepsy test in mice, and 3) apomorphine (1 mg/kg, ip)-induced hypothermia in mice. Both derivatives induced cataleptic behavior (40 mg/kg, ip) and a hypothermic response (30 mg/kg, ip) which was not prevented by haloperidol (0.5 mg/kg, ip). Compound 5 (30 mg/kg, ip) also presented a synergistic hypothermic effect with apomorphine (1 mg/kg, ip). Only compound 4 (30 mg/kg, ip) significantly blocked the amphetamine-induced stereotypy in rats. The N-phenylpiperazine derivatives 4 and 5 seem to have a peculiar profile of action on dopaminergic functions. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behaviors. However, their hypothermic effect is compatible with the stimulation of dopaminergic function which seems not to be mediated by D2/D3 receptors.
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PMID:Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives. 1271 82

SSR181507 ((3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane that displays antagonist activity at dopamine D(2) receptors and agonist activity at 5-HT(1A) receptors. SSR181507 antagonized apomorphine-induced climbing in mice and stereotypies in rats (ED(50) of 2 and 3.4 mg/kg i.p., respectively) and blocked D-amphetamine-induced hyperlocomotion in rats at lower doses (0.3-1 mg/kg i.p.). At 1-10 mg/kg, it was found to disrupt active avoidance in mice. SSR181507 did not induce catalepsy in rats (MED>60 mg/kg i.p.) and antagonized (3-10 mg/kg i.p.) haloperidol-induced catalepsy. SSR181507 was also active in two models sensitive to antidepressant/anxiolytic drugs: in a guinea-pig pup/mother separation test, it decreased (1-3 mg/kg i.p.) the time spent vocalizing during the separation episode, and in a lithium-induced taste aversion procedure in rats, it partially reversed (3 mg/kg i.p.) the decrease of intake of a saccharin solution. Furthermore, SSR181507 increased (3 mg/kg i.p.) the latency time to paradoxical sleep in rats, an effect commonly observed with antidepressants. Coadministration of the selective 5-HT(1A) blocker SL88.0338 produced catalepsy and antagonized the effects of SSR181507 in the depression/anxiety tests, confirming the view that activation of 5-HT(1A) receptors confers an atypical profile on SSR181507, and is responsible for its antidepressant/anxiolytic properties. Finally, SSR181507 (1-3 mg/kg) did not affect memory performance in a Morris water maze task in rats. The pharmacological profile of SSR181507 suggests that it should control the symptoms of schizophrenia, in the absence of extrapyramidal signs and cognitive deficits, with the additional benefit of antidepressant/anxiolytic activities.
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PMID:SSR181507, a dopamine D2 receptor antagonist and 5-HT1A receptor agonist. II: Behavioral profile predictive of an atypical antipsychotic activity. 1290 93

1-(2-ethoxy-phenyl)-4-[3-(3-thiophen-2-yl-isoxazolin-5-yl)-propyl]-piperazine (KCH-1110), has a high affinity for human dopamine D3 (hD3) receptor (Ki=1.28 nM) with about 90-fold selectivity over the human dopamine D2L (hD2L) receptor. Antipsychotic or antidopaminergic activity of KCH-1110 was investigated in the models for the positive symptoms of schizophrenia, apomorphine-induced climbing and cocaine-induced hyperlocomotion, in mice. Intraperitoneal (i.p.) or oral (p.o.) administration of KCH-1110 potently inhibited the apomorphine-induced cage climbing without any rotarod ataxia in mice. Cocaine-induced hyperactivity was also antagonised by KCH-1110. In addition, KCH-1110 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT in mice. KCH-1110 did not induce catalepsy in mice, but at much higher doses only a slight catalepsy response was shown. Although high doses of KCH-1110 significantly enhanced serum prolactin secretion in rats, low dose of KCH-1110 did not increase prolactin levels in rats. The present studies, therefore, suggest that KCH-1110 is a potent and relatively selective dopamine D3 receptor antagonist with antipsychotic actions.
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PMID:Pharmacological actions of a novel and selective dopamine D3 receptor antagonist, KCH-1110. 1452 27

Catatonia is a frequent psychomotor syndrome, which has received increasing recognition over the last decade. The assessment of the catatonic syndrome requires systematic rating scales that cover the complex spectrum of catatonic motor signs and behaviors. The Catatonia Rating Scale (CRS) is such an instrument, which has been validated and which has undergone extensive reliability testing. In the present study, to further validate the CRS, the items composing this scale were submitted to principal components factor extraction followed by a varimax rotation. An analysis of variance (ANOVA) was performed to assess group differences on the extracted factors in patients with schizophrenia, pure mania, mixed mania, and major depression (N=165). Four factors were extracted, which accounted for 71.5% of the variance. The factors corresponded to the clinical syndromes of (1) catatonic excitement, (2) abnormal involuntary movements/mannerisms, (3) disturbance of volition/catalepsy, and (4) catatonic inhibition. The ANOVA revealed that each of the groups showed a distinctive catatonic symptom pattern and that the overlap between diagnostic groups was minimal. We conclude that this four-factor symptom structure of catatonia challenges the current conceptualization, which proposes only two symptom subtypes.
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PMID:Factor analysis of the catatonia rating scale and catatonic symptom distribution across four diagnostic groups. 1461 Jul 26

Prepulse inhibition (PPI) of acoustic startle is decreased in unmedicated schizophrenia patients and similar deficits can be induced in rats through pharmacological, environmental, or neuroanatomical manipulations. Recently, we reported that Brattleboro (BB) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in PPI homologous to those observed in schizophrenia patients. We also reported that PPI deficits in BB rats could be reversed by chronic but not acute administration of 0.5 mg/kg haloperidol. No other dose or drug was tested in that experiment. In this study, we tested the effects of acute subcutaneous administration of several doses of haloperidol as well as the second-generation antipsychotic, clozapine, and the putative novel antipsychotic, PD149163, a neurotensin mimetic that crosses the blood-brain barrier. Consistent with our previous report, BB rats exhibited PPI deficits compared to LE rats and none of the doses of haloperidol produced a significant effect on this PPI deficit. In contrast, 10 and 15 mg/kg of clozapine and all the doses of PD149163 tested reversed the PPI deficits in BB rats. In addition, haloperidol, but not clozapine or PD149163 produced significant catalepsy in BB rats, supporting the notion that PD149163 has a profile consistent with atypical antipsychotics and providing support for the predictive validity of the PPI results. These results further strengthen the notion that the BB rat is a useful predictive model of antipsychotic efficacy and suggest that this model may differentiate between antipsychotics belonging to different therapeutic categories, for example, first- and second-generation agents.
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PMID:Reversal of sensorimotor gating deficits in Brattleboro rats by acute administration of clozapine and a neurotensin agonist, but not haloperidol: a potential predictive model for novel antipsychotic effects. 1476 Mar 94

The first compounds showing efficacy in the treatment of schizophrenia and other psychotic disorders was chlorpromazine, an anti-histaminic compound casually observed to possess antipsychotic effects. The discovery of the real mechanism of action of antipsychotic substances dates back to the 1960s, when researchers found that these compounds act as dopamine receptor antagonists. Unfortunately, this type of drugs cannot block the D2 receptors only in the mesolimbic dopaminergic pathway (which mediates their therapeutic effects), because of their non-selective D2 receptor blockage in both the mesolimbic and striatal regions, and the consequent appearance of side effects related to striatal interaction in the same dosage range as is needed for the therapeutical effects. Clozapine, discovered in the early 1970s, seemed to represent the solution to contrast these side effects, as it possesses antipsychotic activity without inducing extrapyramidal disorders in humans or catalepsy in rats; for this reason, it was defined as an "atypical" antipsychotic drug. Later, other beneficial properties, such as improvement of negative symptoms and of cognitive dysfunction and efficacy in neuroleptic-resistant schizophrenia, were included in the definition of "atypical". In recent years, the appearance of new atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone) has opened new ways to therapy. The aim of this paper is to review literature about newer antipsychotics, focusing on their advantages in terms of efficacy and side effect profiles when compared to classical and older atypical antipsychotics, and to evaluate the efficacy of the different new antipsychotics when compared to one another.
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PMID:New antipsychotics and schizophrenia: a review on efficacy and side effects. 1496 36

D4 is the last receptor cloned among D2 receptor subtypes. Since clozapine has a high affinity to D4 receptors that exist abundantly in the hippocampus and frontal cortex, it is expected that the atypical clinical profiles of clozapine are associated with its blocking action to D4 receptors. Although D4 receptor functions have not been fully investigated, cognitive function of the brain may be associated with D4 receptors. D4 antagonists have only a weak inhibitory effect on the hyperactivity elicited by psychostimulants but induce no catalepsy or prolactin secretion. Previous positive studies on the elevation of the D4 receptors in the striatum of schizophrenia as well as on the association between D4 receptor polymorphism and schizophrenia have been followed by negative findings. Two D4 antagonists (L-745,879 and fananserine) failed to show clinical efficacy in schizophrenia. One of the major difficulties in D4 research is that no selective D4 ligands are available. Although D4 receptors may not play a major role in schizophrenia, they are expected to have a certain effect on frontotemporal function, such as cognition and negative symptoms of schizophrenia.
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PMID:[Functional role of dopamine D4 receptor in schizophrenia]. 1502 26

An involvement of glutamatergic transmission in schizophrenia has been postulated for several years. According to that view, hypofunction of NMDA receptors and a compensatory increase in glutamate release which overstimulates non-NMDA receptors contributes to psychotic symptoms. Therefore, potential antipsychotic drugs are searched for among compounds which block AMPA receptors and inhibit glutamate release. (R,S)-3,4-dicarboxyphenylglycine [(R,S)-3,4-DCPG] is a mixed antagonist of AMPA receptors and agonist of an autoreceptor, i.e. metabotropic glutamate receptor 8. The aim of the study was to look for putative antipsychotic properties of (R,S)-3,4-DCPG in the model of locomotor stimulation induced by amphetamine or phencyclidine in mice. Moreover, a risk of extrapyramidal side-effects induced by this compound was examined, as capability to induce catalepsy in the bar test and to increase the proenkephalin mRNA expression, measured autoradiographically in striatal slices by in situ hybridization. (R,S)-3,4-DCPG (80 mg/kg i.p.) decreased the amphetamine (2.5 mg/kg s.c.)-but not phencyclidine (3 mg/kg s.c.)-induced hyperactivity. That dose of (R,S)-3,4-DCPG did not decrease the spontaneous locomotor activity of mice. However, a dose of 100 mg/kg ip of that compound evoked catalepsy and enhanced the catalepsy and striatal proenkephalin mRNA expression induced by haloperidol (1-2 mg/kg i.p.). The study seems to suggest that (R,S)-3,4-DCPG may possess antipsychotic properties at doses close to those evoking extrapyramidal side-effects which speaks for its rather typical than atypical neuroleptic profile.
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PMID:Potential antipsychotic and extrapyramidal effects of (R,S)-3,4-dicarboxyphenylglycine [(R,S)-3,4-DCPG], a mixed AMPA antagonist/mGluR8 agonist. 1521 59

Neuroleptics are extensively used in the treatment of schizophrenia and other affective disorders. Unfortunately their use is often associated with distressing side effects involving the extrapyramidal tract, such as Parkinsonism and tardive dyskinesia. Neuroleptic-induced catalepsy has long been used as a model for extrapyramidal side effects such as Parkinsonian-like bradykinesia associated with antipsychotic use in humans. In the present study, haloperidol (2 mg/kg i.p.) was administered to mice to induce catalepsy and cataleptic response was measured for the next 4 h at 1 h intervals. Haloperidol treatment in mice induced a strong cataleptic state within 1 h of injection, reaching a maximal plateau after 2 h and lasting for 4 h. Vehicle-treated animals did not display catalepsy as they remained less than 5 sec on the bar at each time point. Pretreatment with quercetin dose-dependently (25-100 mg/kg p.o.) reduced the catalepsy score in haloperidol-treated animals. A dose response study of quercetin showed a characteristic U-shaped response curve, with maximum suppression observed at a dose of 100 mg/kg. On increasing the dose of quercetin to 300 mg/kg, no statistically significant difference in catalepsy score was observed compared with the haloperidol-treated group. In conclusion, the findings of the present study strongly suggest that quercetin can be screened as a potential drug candidate or as an adjuvant for the treatment of neuroleptic-induced extrapyramidal side effects.
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PMID:Quercetin, a bioflavonoid, reverses haloperidol-induced catalepsy. 1531 9


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