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)

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs and that 5-hydroxytryptamine (5-HT2) receptor antagonists produce improvements of the negative symptoms of schizophrenia. [1-(Cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr] (DuP 734) is a novel compound with high affinity for the sigma (Ki = 10 nM) and 5-HT2 (Ki = 15 nM) receptors, but low affinity for dopamine receptors (Ki > 1000 nM) as well as 33 other receptors, ion channels and second messenger systems in vitro. DuP 734 did not inhibit the synaptosomal uptake of dopamine, 5-HT or norepinephrine. Oral administration of DuP 734 potently blocked 5-hydroxy-L-trytophan (5-HTP)-induced head twitch in the rat (ED50 = 6.5 mumol/kg), indicating 5-HT2 antagonist activity. Extracellular single-unit recording studies demonstrated that DuP 734 antagonized the effect of the selective sigma ligand (+)-3-(3-hydroxyphenyl-N-(1-propyl) piperidine [(+)-3-PPP] on dopamine neuronal activity in the substantia nigra of the rat with an ED90 of 3.6 mumol/kg i.v. The sigma receptor agonists (+)-SKF 10,047 and phencyclidine both elicited rotational behavior in rats with unilateral lesion of the substantia nigra. The rotational behavior induced by either (+)-SKF 10,047 or phencyclidine was dose-dependently antagonized by DuP 734 with oral ED50 of 8.7 and 19.6 mumol/kg, respectively. The 5-HT2 receptor antagonist ICI 169,369, even at high doses (up to 33 mumol/kg, s.c.), did not antagonize the rotational behavior induced by (+)-SKF 10,047.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)- piperidine HBr], a sigma and 5-hydroxytryptamine2 receptor antagonist: receptor-binding, electrophysiological and neuropharmacological profiles. 136 72

The psychotomimetic effects of certain cycloalkyls and benzomorphans that interact with sigma receptors has led to the hypothesis that these sites may be important in the etiology of schizophrenia. DuP 734 [1-(cyclopropylmethyl)-4-(2'-(4''-fluoro-phenyl)-2'-oxoethyl) piperidine HBr] is a novel sigma receptor ligand. The receptor binding specificity and neuroanatomical distribution of [3H]DuP 734-labeled sigma receptors in guinea pig brain were examined using quantitative autoradiography. [3H]DuP 734 binding (10 microM haloperidol displaceable) to slide-mounted sections of guinea pig brain was saturable and of high affinity (Ki = 3.9 nM). Competition studies, under conditions identical to those used to visualize the receptor, yielded the following rank order of potency: DuP 734 > haloperidol > (+)-pentazocine > (-)-butaclamol > DTG > (+)-SKF 10,047 > (+)-3-PPP > (-)-pentazocine > (+)-butaclamol > U50,488H > (-)-SKF 10,047 > cinanserin > PCP >> MK801, sulpiride. High densities of [3H]DuP 734 binding sites displaceable by haloperidol were present in the limbic system, in particular the dorsal and ventral bands of Broca as well as the ventral pallidum. Within the hippocampus, the pyramidal layers were sparsely labeled, while higher densities of binding sites were evident in the dentate gyrus. The frontal cortex, the mammillary complex of the hypothalamus, the central gray and red nucleus of the midbrain, the pontine reticular nucleus, the Purkinje cell layer of the cerebellum and dorsal and ventral horns, as well as the central gray matter of the spinal cord, all showed enrichments of [3H]DuP 734 binding sites. Lower levels of binding were present in the other regions of the cerebral cortex including parietal, pyriform, occipital, cingulate cortex, as well as the basal ganglia, and negligible specific binding was present in the white matter tracts. The kinetic and pharmacological characteristics and distribution of [3H]DuP 734 binding sites in brain are similar to those previously reported for sigma receptors.
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PMID:Autoradiographic identification and characterization of sigma receptors in guinea pig brain using [3H]1(cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'-oxoethyl) piperidine ([3H]DuP 734), a novel sigma receptor ligand. 148 5

It is no longer tenable to attribute all the antipsychotic action of antipsychotic drugs to dopamine (DA) D2 receptor blockade and subsequent development of depolarization inactivation of the mesolimbic or mesocortical DA neurons. The chief evidence for this position is that clozapine (CLOZ) does not differ from typical antipsychotic drugs in these regards but is more effective than typical neuroleptic drugs. The mechanism of action of atypical antipsychotic drugs related to CLOZ may involve reduction of dopaminergic activity in the mesolimbic system by a variety of mechanisms, including D1 and D2 receptor blockade. Relatively higher affinity for the serotonin (5HT)2 receptor than for the D2 receptor may also be important to the action of CLOZ-like compounds. Enhanced DA release in the mesocortical system may be relevant to the effectiveness of these agents in treating negative symptoms. Several other classes of new agents alter the dopaminergic system by means of alternative mechanisms. Partial DA agonists may modulate DA neurotransmission more adequately than pure antagonists by producing a mix of direct agonist and antagonistic effects. DA autoreceptor agonists and 5HT3 antagonists appear to act by diminishing the release of DA from some, but not all, DA neurons. Substituted benzamides are "pure" D2 antagonists with some in vivo selectivity for limbic D2 over striatal D2 receptors. Highly selective D1 antagonists have been proposed to produce equivalent antipsychotic activity and fewer extrapyramidal symptoms than D2 antagonists. Antagonists of the recently identified D3 receptors are being sought. Excessive stimulation of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, leading to neurotoxicity or diminished activation of this receptor, is the target of novel approaches to treating schizophrenia. Phencyclidine (PCP) antagonists that would activate the NMDA receptor and sigma receptor antagonists are of interest as antipsychotic agents. Therapeutic strategies for treating schizophrenia, schizophrenia-related disorders, and other psychoses will likely be genuinely diverse in the next decade.
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PMID:The mechanism of action of novel antipsychotic drugs. 167 53

Based on commonalities between peripheral blood "immunocytes" and central nervous system cells (both have receptors for endorphins, enkephalins, dopamine, acetylcholine, etc.) blocking of potassium ion channels in both brain cell synaptosome and suppressor T cells, and common sharing of antigenic determinants on one or another immunocyte and one or another CNS cells, we postulated that peripheral blood immunocytes can be used to study CNS mechanisms. In the present studies we used peripheral blood lymphocytes to study the effects of phencyclidine (PCP) on various receptors. This agent causes a permanent psychosis similar to chronic schizophrenia in a small percent of users. We observed similar effects in binding to sigma receptors, inhibition of binding and reversibility of binding in receptors of both human peripheral blood receptors and the mouse neuroblastoma, a hamster brain cell hybrid clone. The results are complete with the hypothesis that some cases of schizophrenia are immunologically mediated, perhaps due to antibodies to the sigma receptor. Alternatively, immunologic deficiency might hinder elimination of neurotropic viruses which in genetically predisposed individuals bind to and block the sigma receptor. Functional deficiency of the brain cell equivalent of lymphocyte suppressor T cells by one or another immunologic mechanisms or an excess of T helper cells might also cause schizophrenia by causing an excess of normal brain "B-cell equivalent cell" output response to sensory input.
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PMID:Sigma receptors and autoimmune mechanisms in schizophrenia: preliminary findings and hypotheses. 609 18

The receptor binding specificity and neuroanatomical distribution of [3H]NE-100 (N, N-dipropyl-2-[4-methoxy-3-(2- phenylethoxy) phenyl] ethylamine monohydrochloride)-labeled sigma receptor in guinea pig brain were examined using quantitative autoradiography. NE-100 potently inhibited [3H]NE-100 binding to slide-mounted sections of guinea pig brain with the IC50 value of 1.09 nM, therefore, NE-100 apparently has high affinity binding sites. Competition studies, under conditions similar to those used to visualize the receptor, yielded the following rank order of potency: NE-100 > haloperidol > DuP734 > (+)pentazocine >> (-)pentazocine. Non-sigma ligands such as phencyclidine (PCP), MK-801 and (-)sulpiride had negligible affinities for [3H]NE-100 binding sites. High densities of [3H]NE-100 binding sites displaceable by haloperidol were present in the granule layer of the cerebellum, the cingulate cortex, the CA3 region of the hippocampus, the hypothalamus and the pons. The distribution of [3H]NE-100 binding sites was consistent with that of [3H](+)pentazocine, a sigma 1 ligand. These sigma sites may possibly be related to various aspects of schizophrenia.
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PMID:Autoradiographic characterization of binding sites for [3H]NE-100 in guinea pig brain. 747 36

The discovery of chlorpromazine led to rapid progress in drug therapy for schizophrenia. However, conventional neuroleptics frequently induce EPS and tardive dyskinesia in addition to the drawback of having little effect against negative symptoms. New types of atypical antipsychotics has been actively developed in Japan to overcome these drawbacks. Firstly, serotonin-dopamine antagonist (SDA) is most actively developed. Eight SDAs have been introduced into clinical trials: risperidone's trials have been finished and a NDA has been filed, Org 5222 has been dropped because of worsening of significant cases, and 6 SDAs (SM-9018, sertindole, seroquel, AD-5423, ziprasidone and olanzapine) are now under development. Secondly, OPC-14597, a unique atypical antipsychotic has been advanced to the phase 3 study, which has both DA autoreceptor-agonistic and D2-receptor blocking actions. Thirdly, we have much interest in NE-100, a selective sigma receptor antagonist which potently suppresses the phencyclidine-induced behaviors. Finally. a 5-HT3 receptor antagonist, alosetron was already dropped because it showed no antipsychotic effects, although it was introduced with great expectations. We hope that as many as possible new antipsychotics will be approved for the battle against schizophrenia.
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PMID:[Recent progress in development of psychotropic drugs (2)--antipsychotics]. 758 13

Phencyclidine (PCP), in a dose of 15 mg/kg, produced delayed cognitive dysfunction (at 24 h) in rats subjected to water maze tasks. At 24 h after PCP administration, ataxia, hyperlocomotion and stereotyped behavior were not induced. NE-100, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-enthylamine monohydrochloride, a selective and potent sigma receptor ligand, was administered orally 10 min after PCP administration or 15 min before the first trial (24 h after PCP administration). In both cases, NE-100 dose-dependently attenuated the delayed cognitive dysfunction induced by PCP. As these findings show that ingestion of PCP led to delayed cognitive dysfunction similar to the cognitive signs of psychosis seen in humans, NE-100 is being further studied for possible treatment of subjects with schizophrenia.
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PMID:Effect of NE-100, a novel sigma receptor ligand, on phencyclidine- induced delayed cognitive dysfunction in rats. 760 28

1. Phencyclidine (PCP) reduces the latency of rats diving into a water-filled pool from a hidden platform, without stereotyped behavior. 2. The sigma-selective ligand, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethyl-amine monohydrochloride), attenuates the effects of PCP in this procedure. 3. The serotonin2 (5-HT2) antagonist, ritanserin, and the sigma receptor ligands, 1-(cyclopropylmethyl)-4-[2'(4"-fluorophenyl)-2'-oxoethyl]- piperidine HBr (Dup734), 4-[2'-(4"-cyanophenyl)-2'-oxoethyl]-1- (cyclopropylmethyl)piperidine (XJ448), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY14802) and rimcazole similarly attenuate the effects of PCP. 4. The dopamine D2/sigma ligands, haloperidol and cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-methoxy-5-chloro-4- methylaminobenzamide (YM-09151-2) completely reverse the effects of PCP, whereas the same dose ranges of these drugs produce sedation. 5. The dopamine D2-selective antagonist, sulpiride, has no apparent effect on the PCP latency to the rat dive. 6. Thus, PCP-induced diving behavior was improved by sigma ligands and the 5-HT2 antagonist. This model of negative symptoms in an experimental animal will facilitate experiments on drug treatments for schizophrenia.
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PMID:The sigma-selective ligand NE-100 attenuates the effect of phencyclidine in a rat diving model. 771 58

The theoretical role of sigma receptors in psychosis has led to the development of selective sigma receptor ligands as potential antipsychotic agents. BMY 14802 has its most potent binding at the sigma binding site, with some degree of serotonin subtype 1A and negligible dopamine receptor binding. It is atypical of standard neuroleptics in that it does not induce catalepsy in rats. It has been shown to have efficacy in animal models of psychosis. It was hypothesized that the drug would have antipsychotic effects in humans without producing the extrapyramidal side effects typical of standard neuroleptics. We report here the results of an uncontrolled, multicenter safety and efficacy study of patients with acute exacerbations of schizophrenia treated with BMY 14802. After 1 week of single-blind placebo treatment, 28 patients were treated with BMY 14802 (up to 3000 mg/day) for up to 4 weeks. There was no significant improvement in psychiatric symptoms, as measured by the total Brief Psychiatric Rating Scale scores or Clinical Global Improvement. There were no changes in involuntary movements, as measured by the Abnormal Involuntary Movement Scale, or in extrapyramidal symptoms as measured by the Simpson-Angus Scale.
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PMID:BMY 14802, a sigma receptor ligand for the treatment of schizophrenia. 791 21

Neuropeptide Y is a 36-amino acid peptide that is widely distributed in the brain. Recently, three neuropeptide Y receptor subtypes were discovered with the aid of peptidergic agonist analogs of neuropeptide Y. Many researchers reported that neuropeptide Y might be involved in locomotor activity, eating behavior, stress responses, memory processing, circadian rhythms, blood pressure and neuroendocrine functions. It was also reported to interact with sigma receptor and corticotropin-releasing factor. Clinical evidence suggests that neuropeptide Y might be related to depression, schizophrenia, anorexia nervosa and Alzheimer's disease. In this review, central distribution and receptor subtypes of neuropeptide Y, its physiological action and its levels in cerebrospinal fluid and plasma in psychiatric and neurological illnesses are described.
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PMID:[Neuropeptide Y: psychopharmacological and clinical aspects]. 794 76


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