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)

Sigma (sigma) receptors are expressed in the brain as well as endocrine and immune systems. Several antipsychotic drugs such as haloperidol and pentazocine can bind to the sigma receptor, which is believed to play important roles in the pathogenesis of schizophrenia by as yet unknown mechanisms. Two subtypes of sigma receptors (sigma 1 and sigma 2) have been identified, and the sigma 1 receptor was cloned. The chronic administration of haloperidol to guinea pigs produced a marked inhibition of the binding to sigma 1 receptor, but did not change sigma 2-receptor binding. Scatchard analysis demonstrated that the inhibition was due to a reduction in the number of binding sites without changes in the affinity. The treatment with haloperidol also did not affect sigma 1-receptor mRNA detected by the RNase protection assay. The treatment of rats with haloperidol inhibited sigma 1-receptor binding to a much lesser extent than that to guinea pigs. These finding suggest that haloperidol or its metabolite, reduced haloperidol, which is produced in greater quantity in humans and guinea pigs than in rats and mice, might influence protein translation or modification of sigma 1-receptor without changing the transcriptional activity. The mechanisms through which sigma receptors could be differently regulated in vivo by chronic treatment with haloperidol may contribute to the therapeutic efficacy of haloperidol.
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PMID:[Functional characterization of a sigma receptor and its gene expression by haloperidol]. 1056 66

MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]++ +methy l-2-pyrrolidinone L-tartrate) is a novel selective sigma receptor ligand, currently being developed for the treatment of schizophrenia. MS-377 showed anti-phencyclidine (PCP), anti-dopaminergic and anti-serotonergic activities, and we anticipated that the anti-psychotic activities of MS-377 were associated with sigma(1) receptors. However, its pharmacological profile is partly distinct from those of selective sigma(1) receptor ligands. Thus, one of the possible speculations is that MS-377 has another site of action. In the present study, we examined the binding properties of radiolabeled MS-377 ([3H]MS-377) to rat brain membranes. [3H]MS-377 showed saturable and reversible binding to rat brain membranes. Scatchard plot and Hill plot from saturation studies were linear, with K(d) of 15.2+/-6.6 nM, B(max) of 599.4+/-58.6 fmol/mg protein and Hill coefficient of 1.01+/-0.01, indicating that [3H]MS-377 bound to a single high-affinity site in rat brain membranes. Displacement studies revealed that the other sigma reference compounds with different structures inhibited the specific binding of [3H]MS-377 in a competitive manner. Stereoselectivity was observed for the inhibition of [3H]MS-377 binding, (+)-isomers were more potent than (-)-isomers. Non-sigma receptor ligand PCP showed weak inhibition of [3H]MS-377 binding. The rank order of potency for the sigma reference compounds to displace [3H]MS-377 binding were as following: haloperidol>MS-377=(+)-pentazocine>DTG (1, 3-Ditolylguanidine)=(-)-pentazocine>BMY14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyramidinyl)-1-piperazine butanol)>(+)-SKF-10,047>(-)-SKF-10,047=PCP. These results suggested that the MS-377 selectively binds to sigma binding site with high affinity in rat brain membranes. Therefore, the anti-psychotic activities of MS-377 are attributable to association with sigma(1) receptors.
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PMID:Binding properties of [3H]MS-377, a novel sigma receptor ligand, to rat brain membranes. 1091 84

Sigma receptors have recently been the target of drug development related to psychiatric disorders, including schizophrenia and depression, as well as cognitive enhancers. This paper focused on the sigma-receptor-mediated modulation of neuronal activity, especially the effects on aminergic neuron and hippocampal neuron activity. Dopaminergic neuron activities in the substantia nigra and ventral tegmental area (VTA) are variously modified by the systemic administration of sigma ligands. When applied with microiontophoresis, they are reported to increase dopaminergic neuron activity in the VTA. This activity may be involved in the psychotropic or antipsychotic effects of these ligands. Moreover, serotonergic neurons in the raphe nucleus and noradrenergic neurons in the locus coeruleus were activated by sigma ligands. These effects are probably related to the antidepressant activity of sigma receptor ligands. In the hippocampus, sigma ligands suppressed CA1 neuronal activity in vitro. The effects were suggested to be due to an increase in the threshold of action potential and decreased synaptic transmission efficacy. NMDA receptor function was modified in biphasic fashion related to doses of sigma ligands, that is, a lower dose facilitated the NMDA receptor functions, and a higher dose inhibited them. These effects on the hippocampal neurons may contribute to their neuroprotective and antiamnesic actions. Further studies are needed to elucidate the relation between the physiological function of sigma receptor and psychiatric diseases by the use of sigma receptor ligands and molecular techniques.
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PMID:[Modulation of neuronal activities in the central nervous system via sigma receptors]. 1191 6

The sigma receptor was originally proposed to be a subtype of the opioid receptor. However, it is now clear that sigma receptors are unique non-opioid, non-phencyclidine brain proteins. Two types of sigma receptor exist, the sigma-1 receptor and the sigma-2 receptor. sigma-1 receptors have been cloned and their distribution, physiological functions and roles in signal transduction were recently characterised. Certain sex hormones in the brain (neurosteroids) are known to interact with sigma-1 receptors. sigma-1 receptors regulate glutamate NMDA receptor function and the release of neurotransmitters such as dopamine. They are thus proposed to be involved in learning and memory as well as in certain neuropsychiatric disorders. Selective sigma-1 receptor ligands have been suggested to represent a new class of therapeutic agents for neuropsychiatric disorders, although none have yet been introduced into therapeutic use. Early studies showed that psychotomimetic benzomorphans, as well as several antipsychotics, can bind to sigma-1 receptors. As a result of these findings, sigma-1 receptor ligands have been proposed as being of potential use in the treatment of schizophrenia. Nevertheless, the relationship of sigma-1 receptors to the underlying pathogenesis of schizophrenia is still unclear. sigma-1 receptor ligands have failed to improve acute psychotic symptoms of schizophrenia in clinical trials, but, interestingly, a few studies have shown an improvement in negative symptoms in schizophrenic patients. A number of preclinical studies have shown that selective agonists of sigma-1 receptors affect higher-ordered brain functions such as learning and memory, cognition and mood. These studies indicate that sigma-1 receptor agonists may exert therapeutic effects in depression and senile dementia. Indeed, the sigma-1 receptor agonist igmesine, has been shown to improve depression in a clinical trial. The most distinctive feature of the action of sigma-1 receptor ligands is their "modulatory" role. In behavioural studies of depression and memory, they exert beneficial effects only when brain functions are perturbed. Given the recently accumulated preclinical and clinical data, it is time to reconstruct the concept of sigma-1 receptors and the associated pathophysiological conditions that ligands of these receptors target. This would allow clinical trials to be performed more efficiently, and the results may confirm a long-speculated possibility that sigma-1 receptor ligands represent a new class of therapeutic agents for neuropsychiatric disorders.
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PMID:Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. 1508 13

More than 20 years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.
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PMID:Sigma receptors: biology and therapeutic potential. 1519 33

Sigma (sigma) receptors, first defined as a subclass of opioid receptors, later confounded with the high affinity phencyclidine (PCP) binding sites, now are regarded as unique binding sites, distinct from opiate and PCP receptors, and related to higher brain function. The investigation of functional significance of sigma receptors in the brain has been hampered for many years by relative lack of specific tool drugs and by the unavailability of their coherent classification into postulated agonists and antagonists. However, a potential involvement of sigma receptors in psychotic disorders was first suggested soon after their discovery. The sigma receptors are classified into two subtypes, sigma (1) and sigma (2) receptors, of which the first was recently cloned from rodent and human tissues while the second has not yet been fully characterized. Although the precise mechanism of the functional response of these receptors is still uncertain, it is accepted that sigma receptors can modulate a number of central neurotransmitter systems, including noradrenergic, glutamatergic and dopaminergic ones. The sigma receptors have been postulated to be involved in numerous pharmacological and physiological functions, including motor disorders, psychotic disorders, neuroprotective mechanisms. In the last years, a number of compounds with a high affinity and selectivity for sigma binding sites have been discovered and investigated for their therapeutic potential. In this review, we try to summarize the behavioral effects of sigma receptor ligands that have been described, and their activity in animal models related to some brain disorders, especially schizophrenia and affective disorders.
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PMID:Behavioral pharmacology of sigma-ligands. 1554 84

Neurosteroids, such as dehydroepiandrosterone (DHEA) and DHEA-sulfate (the most abundant steroid in the body), regulate neuronal functions by influencing neuronal excitability. Prominent effects are exerted on the gamma-aminobutyric (GABA) receptors. DHEA has demonstrated efficacy in improvement of mood in humans, especially in middle-aged and elderly individuals. In the author's study, administering DHEA to patients with schizophrenia who had moderate to severe negative symptoms and who were maintained on antipsychotic medications induced significant improvement, more so in women and corresponding to increased plasma levels of DHEA and DHEA-S. Possible mechanisms of action include enhanced dopamine release, enhanced responsiveness at the N-methyl D-aspartate (NMDA) receptor, facilitation of sigma receptor activity, selective potentiation of dopaminergic neurotransmission, and a general anxiolytic action. Side effects are reviewed, and the currently experimental status of DHEA augmentation is emphasized.
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PMID:Dehydroepiandrosterone (DHEA) augmentation in the management of schizophrenia symptomatology. 1586 21

Esteve is developing E-5842, a sigma1 opioid receptor ligand, as a potential therapy for psychosis. It has completed phase I trials [344879,346244]. As of May 1999, the site and protocol for phase II schizophrenia trials in the UK had been finalized and these were scheduled to begin shortly thereafter, with results likely to be available by the end of 2000 [365516]. E-5842 acted as an atypical antipsychotic in preclinical neurochemical and behavioral tests. Both acute (40 mg/kg ip for 2 h) and chronic (20 mg/kg ip daily for 21 days) administration of E-5842 increased PLC activity and the drug may thus achieve its antipsychotic effects via a signalling pathway involving phosphoinositide second messengers [336324]. E-5842 has a K(i) value of 4 nM at the sigma receptor [306875]. It blocks apomorphine-induced climbing, and antagonizes amphetamine-induced locomotor activity in mice [271405].
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PMID:E-5842 (Laboratories Dr Esteve). 1609 30

Sigma receptors are classified into sigma(1) and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma(1) receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma(2) receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca(2+), and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.
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PMID:Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. 1707 84

The sigma receptors were first classified as a subtype of opioid receptors but later they were found to be a distinct pharmacological entity. Many preclinical and clinical data have indicated that sigma receptor ligands have to be involved in neuropsychiatric disorders, including schizophrenia. Numerous data have suggested that potential antipsychotic activity of sigma ligands results from their "antagonistic" activity. However, the subcellular mechanisms by which sigma ligands exert their effects have not been elucidated in detail, therefore, the terms "agonist" or "antagonist" and their functional implications are not entirely unequivocal. The aim of the present study was to find out if BD 1047, described recently as a selective functional antagonist of sigma receptors, shows antipsychotic activity in animal models predictive of efficacy in schizophrenia. In contrast to rimcazole and panamesine, two selective sigma ligands whose antipsychotic activity was confirmed clinically, BD 1047 did not decrease amphetamine-induced hyperactivity in mice in a statistically significant manner. Likewise, it did not modify the hyperactivity induced by NMDA receptor antagonists, phencyclidine, memantine or dizocilpine. On the other hand, BD 1047 attenuated apomorphine-induced climbing in mice and phencyclidine-induced head twitches in rats, like rimcazole and panamesine did. Summing up, BD 1047 shows a moderate activity in models used in this study suggesting that its usefulness as an antipsychtic drug is doubtful. However, more detailed studies are required for definitive confirmation of this conclusion.
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PMID:Effect of BD 1047, a sigma1 receptor antagonist, in the animal models predictive of antipsychotic activity. 1708 54


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