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1.
Cell ; 176(3): 581-596.e18, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30661753

RESUMO

Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.


Assuntos
Astrócitos/metabolismo , Sistema Nervoso Central/metabolismo , Animais , Sistema Nervoso Central/imunologia , Biologia Computacional/métodos , Encefalomielite Autoimune Experimental/imunologia , Endorribonucleases/metabolismo , Meio Ambiente , Exposição Ambiental/efeitos adversos , Genoma , Genômica , Humanos , Inflamação/metabolismo , Linurona/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores sigma/efeitos dos fármacos , Receptores sigma/metabolismo , Transdução de Sinais , Proteína 1 de Ligação a X-Box/metabolismo , Peixe-Zebra
2.
ACS Chem Neurosci ; 10(3): 1595-1602, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30421909

RESUMO

Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (σ2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimer's disease and schizophrenia. These promising applications coupled with our previous observation that the σ2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild-type mice suggests that modulating σ2R/TMEM97 may also have therapeutic benefits in other neurodegenerative conditions such as traumatic brain injury (TBI). Herein, we report that DKR-1677, a novel derivative of SAS-0132 with increased affinity and selectivity for σ2R/Tmem97 ( Ki = 5.1 nM), is neuroprotective after blast-induced and controlled cortical impact (CCI) TBI in mice. Specifically, we discovered that treatment with DKR-1677 decreases axonal degeneration after blast-induced TBI and enhances survival of cortical neurons and oligodendrocytes after CCI injury. Furthermore, treatment with DKR-1677 preserves cognition in the Morris water maze after blast TBI. Our results support an increasingly broad role for σ2R/Tmem97 modulation in neuroprotection and suggest a new approach for treating patients suffering from TBI.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Proteínas de Membrana/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores sigma/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios/efeitos dos fármacos
3.
Bioorg Med Chem Lett ; 28(19): 3206-3209, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30143421

RESUMO

The sigma receptor (σR) family has been considered mysterious for a long time. In fact, the σ2R subtype has been cloned only recently, revealing its identity as TMEM97, a NPC1-binding protein involved in cholesterol biosynthesis and implicated in the pathogenesis of cancer and neurologic disorders. With the aim of developing new chemical entities gifted with σR affinity, herein we report the design and synthesis of new piperidine-based alkylacetamide derivatives with mixed affinity towards both σ1 and σ2R subtypes.


Assuntos
Piperidinas/química , Receptores sigma/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Ligantes , Piperidinas/síntese química , Piperidinas/farmacologia
4.
Alzheimers Dement ; 14(6): 811-823, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29291374

RESUMO

INTRODUCTION: AF710B (aka ANAVEX 3-71) is a novel selective allosteric M1 muscarinic and sigma-1 receptor agonist. In 3×Tg-AD mice, AF710B attenuates cognitive deficits and decreases Alzheimer-like hallmarks. We now report on the long-lasting disease-modifying properties of AF710B in McGill-R-Thy1-APP transgenic (Tg) rats. METHODS: Chronic treatment with AF710B (10 µg/kg) was initiated in postplaque 13-month-old Tg rats. Drug or vehicle was administered orally daily for 4.5 months and interrupted 5 weeks before behavioral testing. RESULTS: AF710B long-term treatment reverted the cognitive deficits associated with advanced Alzheimer-like amyloid neuropathology in Tg rats. These effects were accompanied by reductions in amyloid pathology and markers of neuroinflammation and increases in amyloid cerebrospinal fluid clearance and levels of a synaptic marker. Importantly, these effects were maintained following a 5-week interruption of the treatment. DISCUSSION: With M1/sigma-1 activity and long-lasting disease-modifying properties at low dose, AF710B is a promising novel therapeutic agent for treating Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Receptores sigma/efeitos dos fármacos , Compostos de Espiro/farmacologia , Tiazolidinas/farmacologia , Administração Oral , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/patologia , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Ratos , Ratos Transgênicos , Compostos de Espiro/administração & dosagem , Tiazolidinas/administração & dosagem
5.
Alcohol Clin Exp Res ; 42(2): 338-351, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29205397

RESUMO

BACKGROUND: Reduced dopamine D2 receptor (D2R) ligand binding has repeatedly been demonstrated in the striatum of humans with alcohol use disorder (AUD). The attenuated D2R binding has been suggested to reflect a reduced D2R density, which in turn has been proposed to drive craving and relapse. However, results from rodent studies addressing the effects of alcohol drinking on D2R density have been inconsistent. METHODS: A validated alcohol drinking model (intermittent access to 20% alcohol) in Wistar rats was used to study the effects of voluntary alcohol drinking (at least 12 weeks) on the D2R in the striatum compared to age-matched alcohol-naïve control rats. Reverse transcriptase quantitative PCR was used to quantify isoform-specific Drd2 gene expression levels. Using bisulfite pyrosequencing, DNA methylation levels of a regulatory region of the Drd2 gene were determined. In situ proximity ligation assay was used to measure densities of D2R receptor complexes: D2R-D2R, adenosine A2A receptor (A2AR)-D2R, and sigma1 receptor (sigma1R)-D2R. RESULTS: Long-term voluntary alcohol drinking significantly reduced mRNA levels of the long D2R isoform in the nucleus accumbens (NAc) but did not alter CpG methylation levels in the analyzed sequence of the Drd2 gene. Alcohol drinking also reduced the striatal density of D2R-D2R homoreceptor complexes, increased the density of A2AR-D2R heteroreceptor complexes in the NAc shell and the dorsal striatum, and decreased the density of sigma1R-D2R heteroreceptor complexes in the dorsal striatum. CONCLUSIONS: The present results on long-term alcohol drinking might reflect reduced D2R levels through reductions in D2R-D2R homoreceptor complexes and gene expression. Furthermore, based on antagonistic interactions between A2AR and D2R, an increased density of A2AR-D2R heteroreceptor complexes might indicate a reduced affinity and signaling of the D2R population within the complex. Hence, both reduced striatal D2R levels and reduced D2R protomer affinity within the striatal A2AR-D2R complex might underlie reduced D2R radioligand binding in humans with AUD. This supports the hypothesis of a hypodopaminergic system in AUD and suggests the A2AR-D2R heteroreceptor complex as a potential novel treatment target.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Corpo Estriado/efeitos dos fármacos , Etanol/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Consumo de Bebidas Alcoólicas , Animais , Corpo Estriado/metabolismo , Expressão Gênica/efeitos dos fármacos , Masculino , Complexos Multiproteicos/efeitos dos fármacos , Complexos Multiproteicos/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptor A2A de Adenosina/efeitos dos fármacos , Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores sigma/efeitos dos fármacos , Receptores sigma/metabolismo
6.
Behav Brain Res ; 339: 1-10, 2018 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-29129596

RESUMO

The sigma-1 receptor (S1R) is a molecular chaperone which activity modulates several intracellular signals including calcium mobilization at mitochondria-associated endoplasmic reticulum membranes. S1R agonists are potent neuroprotectants against neurodegenerative insults and particularly in rodent models of Alzheimer's disease (AD). We here analyzed whether S1R inactivation modifies vulnerability to amyloid toxicity in AD models. Two strategies were used: (1) amyloid ß[25-35] (Aß25-35) peptide (1, 3, 9nmol) was injected intracerebroventricularly in mice treated repeatedly with the S1R antagonist NE-100 or in S1RKO mice, and (2) WT, APPSweInd, S1RKO, and APPSweInd/S1RKO mice were created and female littermates analyzed at 8 months of age. Learning deficits, oxidative stress, Bax level and BDNF content in the hippocampus were analyzed. Aß25-35 induced learning impairment, oxidative stress, Bax induction and BDNF alteration at lower dose in NE-100-treated mice or S1RKO mice as compared to WT animals. The extent of learning deficits and biochemical alterations were also higher in APPSweInd/S1RKO mice as compared to WT, APPSweInd, and S1RKO animals. S1R inactivation or altered S1R expression augmented the pathological status in pharmacologic and genetic AD mouse models. These observations, in relation with the well-known protective effects of S1R agonists, are coherent with a role of signal amplifier in neurodegeneration and neuroprotection proposed for S1R in AD and related neurodegenerative disorders.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/farmacologia , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores sigma/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/genética , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/metabolismo , Receptores sigma/efeitos dos fármacos , Receptores sigma/genética
7.
Nat Commun ; 8(1): 2228, 2017 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-29263318

RESUMO

Dopamine neurotransmission is highly dysregulated by the psychostimulant methamphetamine, a substrate for the dopamine transporter (DAT). Through interactions with DAT, methamphetamine increases extracellular dopamine levels in the brain, leading to its rewarding and addictive properties. Methamphetamine also interacts with the sigma-1 receptor (σ1R), an inter-organelle signaling modulator. Using complementary strategies, we identified a novel mechanism for σ1R regulation of dopamine neurotransmission in response to methamphetamine. We found that σ1R activation prevents methamphetamine-induced, DAT-mediated increases in firing activity of dopamine neurons. In vitro and in vivo amperometric measurements revealed that σ1R activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission. Consistent with these findings, σ1R activation decreases methamphetamine-induced locomotion, motivated behavior, and enhancement of brain reward function. Notably, we revealed that the σ1R interacts with DAT at or near the plasma membrane and decreases methamphetamine-induced Ca2+ signaling, providing potential mechanisms. Broadly, these data provide evidence for σ1R regulation of dopamine neurotransmission and support the σ1R as a putative target for the treatment of methamphetamine addiction.


Assuntos
Dopaminérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Metanfetamina/farmacologia , Receptores sigma/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Comportamento Animal , Células CHO , Células Cultivadas , Cricetulus , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Células HEK293 , Humanos , Locomoção , Camundongos , Camundongos Knockout , Motivação , Técnicas de Patch-Clamp , Receptores sigma/genética , Receptores sigma/metabolismo , Recompensa
8.
Handb Exp Pharmacol ; 244: 1-11, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28871306

RESUMO

For over 40 years, scientists have endeavored to understand the so-called sigma receptors. During this time, the concept of sigma receptors has continuously and significantly evolved. With thousands of publications on the subject, these proteins have been implicated in various diseases, disorders, and physiological processes. Nevertheless, we are just beginning to understand what sigma proteins do and how they work. Two subtypes have been identified, Sigma1 and Sigma2. Whereas Sigma1 (also known as sigma-1 receptor, Sig1R, σ1 receptor, and several other names) was cloned over 20 years ago, Sigma2 (sigma-2 receptor, σ2 receptor) was cloned very recently and had remained a pharmacologically defined entity. In this volume, we will focus primarily on Sigma1. We will highlight several key subject areas in which Sigma1 has been well characterized as well as (re)emerging areas of interest. Despite the large number of publications regarding Sigma1, several fundamental questions remain unanswered or only partially answered. Most of what we know about Sigma1 comes from pharmacological studies; however, a clearly defined molecular mechanism of action remains elusive. One concept has become clear; Sigma1 is not a traditional receptor. Sigma1 is now considered a unique pharmacologically regulated integral membrane chaperone or scaffolding protein. A number of landmark discoveries over the past decade have begun to reshape the concept of sigma receptors. With the rapid emergence of new information, development of new tools, and changing conceptual frameworks, the field is poised for a period of accelerated progress.


Assuntos
Receptores sigma/metabolismo , Transdução de Sinais , Alcoolismo/metabolismo , Alcoolismo/psicologia , Analgésicos/farmacologia , Animais , Antineoplásicos/farmacologia , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , História do Século XX , História do Século XXI , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Degeneração Neural , Neurônios/metabolismo , Neurônios/patologia , Conformação Proteica , Receptores sigma/química , Receptores sigma/efeitos dos fármacos , Receptores sigma/história , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
9.
Handb Exp Pharmacol ; 244: 163-175, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28667477

RESUMO

Since their proposal in 1976, the concept of sigma1 receptors has been continually evolving. Initially thought to be a member of the opioid receptor family, molecular studies have now identified its genes and established its structure crystallographically. Much effort has now revealed its importance as a chaperone in the endoplasmic reticulum, but its functions extend beyond this. Sigma1 receptors have been associated with a host of signaling systems. Evidence over the past 20 years has established the modulatory effects of sigma1 ligands on opioid systems. Despite their inability to bind directly to opioid receptors, sigma1 ligands can modulate opioid analgesia in vivo and signal transduction mechanisms in vitro. Furthermore, sigma1 receptors can physically associate with GPCRs. Together, these findings show that sigma1 ligands can function as allosteric modulators of GPCR function through their association with the sigma1 receptors, which are in direct physical association with opioid receptors, members of the G-protein coupled family of receptors.


Assuntos
Sistema Nervoso Central/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Receptor Cross-Talk , Receptores Opioides/metabolismo , Receptores sigma/metabolismo , Transdução de Sinais , Analgésicos Opioides/uso terapêutico , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiopatologia , Humanos , Dor/fisiopatologia , Ligação Proteica , Receptor Cross-Talk/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Receptores sigma/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
10.
Handb Exp Pharmacol ; 244: 237-308, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28744586

RESUMO

Sigma1 (also known as sigma-1 receptor, Sig1R, σ1 receptor) is a unique pharmacologically regulated integral membrane chaperone or scaffolding protein. The majority of publications on the subject have focused on the neuropharmacology of Sigma1. However, a number of publications have also suggested a role for Sigma1 in cancer. Although there is currently no clinically used anti-cancer drug that targets Sigma1, a growing body of evidence supports the potential of Sigma1 ligands as therapeutic agents to treat cancer. In preclinical models, compounds with affinity for Sigma1 have been reported to inhibit cancer cell proliferation and survival, cell adhesion and migration, tumor growth, to alleviate cancer-associated pain, and to have immunomodulatory properties. This review will highlight that although the literature supports a role for Sigma1 in cancer, several fundamental questions regarding drug mechanism of action and the physiological relevance of aberrant SIGMAR1 transcript and Sigma1 protein expression in certain cancers remain unanswered or only partially answered. However, emerging lines of evidence suggest that Sigma1 is a component of the cancer cell support machinery, that it facilitates protein interaction networks, that it allosterically modulates the activity of its associated proteins, and that Sigma1 is a selectively multifunctional drug target.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Receptores sigma/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Descoberta de Drogas/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Receptores sigma/genética , Receptores sigma/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
J Nucl Med ; 58(12): 2004-2009, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28572487

RESUMO

The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective σ-1 receptor PET agent 18F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one (18F-FTC-146). Methods: Ten healthy volunteers (5 women, 5 men; age ± SD, 34.3 ± 6.5 y) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/MRI examinations were acquired for up to 3 h after injection (357.2 ± 48.8 MBq). Blood samples were collected, and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions of interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry were estimated. Results: All subjects tolerated the PET/MRI examination well, and no adverse reactions to 18F-FTC-146 were reported. High accumulation of 18F-FTC-146 was observed in σ-1 receptor-dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose of 18F-FTC-146 was 0.0259 ± 0.0034 mSv/MBq (range, 0.0215-0.0301 mSv/MBq). Conclusion: First-in-human studies with clinical-grade 18F-FTC-146 were successful. Injection of 18F-FTC-146 is safe, and absorbed doses are acceptable. The potential of 18F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation.


Assuntos
Azepinas/farmacocinética , Benzotiazóis/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Azepinas/efeitos adversos , Azepinas/síntese química , Benzotiazóis/efeitos adversos , Benzotiazóis/síntese química , Feminino , Voluntários Saudáveis , Humanos , Marcação por Isótopo , Imagem por Ressonância Magnética , Masculino , Imagem Multimodal , Radiometria , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/síntese química , Receptores sigma/efeitos dos fármacos , Receptores sigma/metabolismo , Distribuição Tecidual , Imagem Corporal Total
12.
Basic Clin Pharmacol Toxicol ; 121(6): 471-479, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28654186

RESUMO

Neuropathic pain has proven to be a difficult condition to treat, so investigational therapy has been sought that may prove useful, such as the use of sigma-1 antagonists. Haloperidol (HAL) is a compound that shows a high affinity with these receptors, acting as an antagonist. Therefore, the objective of this study was to demonstrate its effect in an experimental model of neuropathic pain and corroborate its antagonistic action of the sigma-1 receptors under these conditions. BD-1063 was used as a sigma-1 antagonist control, and gabapentin (Gbp) was used as a positive control. The antihyperalgesic and anti-allodynic effects of the drugs were determined after single-dose trials. In every case, the effects increased in a dose-dependent manner. HAL had the same efficacy as both BD-1063 and Gbp. In the analysis of pharmacological potency, in which the ED50 were compared, HAL was the most potent drug of all. The effect of HAL on chronic constriction injury (CCI) rats was reversed by the sigma-1 agonist (PRE-084). HAL reversed the hyperalgesic and allodynic effects of PRE-084 in naïve rats. The dopamine antagonist, (-)-sulpiride, showed no effect in CCl rats. These results suggest that HAL presents an antinociceptive effect via sigma-1 receptor antagonism at the spinal level in the CCl model.


Assuntos
Analgésicos/farmacologia , Antipsicóticos/farmacologia , Constrição Patológica/tratamento farmacológico , Haloperidol/farmacologia , Hiperalgesia/tratamento farmacológico , Aminas/farmacologia , Analgésicos/administração & dosagem , Animais , Antipsicóticos/administração & dosagem , Doença Crônica , Constrição Patológica/complicações , Constrição Patológica/psicologia , Ácidos Cicloexanocarboxílicos/farmacologia , Relação Dose-Resposta a Droga , Gabapentina , Haloperidol/administração & dosagem , Hiperalgesia/etiologia , Hiperalgesia/psicologia , Injeções Espinhais , Masculino , Neuralgia/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Piperazinas/farmacologia , Ratos , Ratos Wistar , Receptores sigma/antagonistas & inibidores , Receptores sigma/efeitos dos fármacos , Sulpirida/uso terapêutico , Ácido gama-Aminobutírico/farmacologia
13.
Handb Exp Pharmacol ; 244: 51-79, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28620761

RESUMO

In the first part of this chapter, we summarize the various pharmacophore models for σ1 receptor ligands. Common to all of them is a basic amine flanked by two hydrophobic regions, representing the pharmacophoric elements. The development of computer-based models like the 3D homology model is described as well as the first crystal structure of the σ1 receptor. The second part focuses on the synthesis and biological properties of different σ1 receptor ligands, identified as 1-9. Monocyclic piperazines 1 and bicyclic piperazines 2 and 3 were developed as cytotoxic compounds, thus the IC50 values of cell growth and survival inhibition studies are given for all derivatives. The mechanism of cell survival inhibition, induction of time-dependent apoptosis, of compound ent-2a is discussed. Experimentally determined σ1 affinity shows good correlation with the results from molecular dynamics simulations based on a 3D homology model. Spirocyclic compounds 4 and 5 represent well-established σ1 receptor ligands. The homologous fluoroalkyl derivatives 4 have favorable pharmacological properties for use as fluorinated PET tracers. The (S)-configured fluoroethyl substituted compound (S)-4b is under investigation as PET tracer for imaging of σ1 receptors in the brain of patients affected by major depression. 1,3-Dioxanes 6c and 6d display a very potent σ1 antagonist profile and the racemic 1,3-dioxane 6c has high anti-allodynic activity at low doses. The arylpropenylamines 7 are very potent σ1 receptor ligands with high σ1/σ2 selectivity. The top compound 7g acts as an agonist as defined by its ability to potentiate neurite outgrowth at low concentrations. Among the morpholinoethoxypyrazoles 8, 8c (known as S1RA) reveals the most promising pharmacokinetic and physicochemical properties. Due to its good safety profile, 8c is currently being investigated in a phase II clinical trial for the treatment of neuropathic pain. The most potent ligand 9e of 3,4-dihydro-2(1H)-quinolones 9 shows promising anti-nociceptive activity in the formalin test.


Assuntos
Analgésicos/farmacologia , Antidepressivos/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Receptores sigma/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/metabolismo , Analgésicos/farmacocinética , Animais , Antidepressivos/síntese química , Antidepressivos/metabolismo , Antidepressivos/farmacocinética , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Receptores sigma/química , Receptores sigma/metabolismo , Relação Estrutura-Atividade
14.
J Pharmacol Exp Ther ; 362(1): 2-13, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28442581

RESUMO

Several N-substituted benztropine (BZT) analogs are atypical dopamine transport inhibitors as they have affinity for the dopamine transporter (DAT) but have minimal cocaine-like pharmacologic effects and can block numerous effects of cocaine, including its self-administration. Among these compounds, N-methyl (AHN1-055), N-allyl (AHN2-005), and N-butyl (JHW007) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane were more potent in antagonizing self-administration of cocaine and d-methamphetamine than in decreasing food-maintained responding. The antagonism of cocaine self-administration (0.03-1.0 mg/kg per injection) with the above BZT analogs was reproduced in the present study. Further, the stimulant-antagonist effects resembled previously reported effects of pretreatments with combinations of standard DAT inhibitors and σ1-receptor (σ1R) antagonists. Therefore, the present study examined binding of the BZT analogs to σRs, as well as their in vivo σR antagonist effects. Each of the BZT analogs displaced radiolabeled σR ligands with nanomolar affinity. Further, self-administration of the σR agonist DTG (0.1-3.2 mg/kg/injection) was dose dependently blocked by AHN2-005 and JHW007 but potentiated by AHN1-055. In contrast, none of the BZT analogs that were active against DTG self-administration was active against the self-administration of agonists at dopamine D1-like [R(+)-SKF 81297, (±)-SKF 82958 (0.00032-0.01 mg/kg per injection each)], D2-like [R(-)-NPA (0.0001-0.0032 mg/kg per injection), (-)-quinpirole (0.0032-0.1 mg/kg per injection)], or µ-opioid (remifentanil, 0.0001-0.0032 mg/kg per injection) receptors. The present results indicate that behavioral antagonist effects of the N-substituted BZT analogs are specific for abused drugs acting at the DAT and further suggest that σR antagonism contributes to those actions.


Assuntos
Benzotropina/análogos & derivados , Benzotropina/farmacologia , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Receptores sigma/efeitos dos fármacos , Animais , Química Encefálica/efeitos dos fármacos , Cocaína/farmacologia , Transtornos Relacionados ao Uso de Cocaína/psicologia , Condicionamento Operante/efeitos dos fármacos , Dopaminérgicos/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Camundongos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Autoadministração
15.
Handb Exp Pharmacol ; 244: 81-108, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28275911

RESUMO

The sigma-1 (σ1) receptor has been associated with regulation of intracellular Ca2+ homeostasis, several cellular signaling pathways, and inter-organelle communication, in part through its chaperone activity. In vivo, agonists of the σ1 receptor enhance brain plasticity, with particularly well-described impact on learning and memory. Under pathological conditions, σ1 receptor agonists can induce cytoprotective responses. These protective responses comprise various complementary pathways that appear to be differentially engaged according to pathological mechanism. Recent studies have highlighted the efficacy of drugs that act through the σ1 receptor to mitigate symptoms associated with neurodegenerative disorders with distinct mechanisms of pathogenesis. Here, we will review genetic and pharmacological evidence of σ1 receptor engagement in learning and memory disorders, cognitive impairment, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease.


Assuntos
Transtornos da Memória/metabolismo , Memória , Degeneração Neural , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Receptores sigma/metabolismo , Animais , Humanos , Ligantes , Memória/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/psicologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Receptores sigma/efeitos dos fármacos , Receptores sigma/genética , Transdução de Sinais
16.
Expert Opin Ther Pat ; 27(5): 565-578, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28051882

RESUMO

INTRODUCTION: Although several molecular targets against cancer have been identified, there is a continuous need for new therapeutic strategies. Sigma Receptors (SRs) overexpression has been recently associated with different cancer conditions. Therefore, novel anticancer agents targeting SRs may increase the specificity of therapies, overcoming some of the common drawbacks of conventional chemotherapy. Areas covered: The present review focuses on patent documents disclosing SR modulators with possible application in cancer therapy and diagnosis. The analysis reviews patents of the last two decades (1996-2016); patents were grouped according to target subtypes (S1R, S2R, pan-SRs) and relevant Applicants. The literature was searched through Espacenet, ISI Web, PatentScope and PubMed databases. Expert opinion: The number of patents related to SRs and cancer has increased in the last twenty years, confirming the importance of this receptor family as valuable target against neoplasias. Despite their short history in the cancer scenario, many SR modulators are at pre-clinical stage and one is undergoing a phase II clinical trial. SRs ligands may represent a powerful source of innovative antitumor therapeutics. Further investigation is needed for validating SR modulators as anti-cancer drugs. We strongly hope that this review could stimulate the interest of both Academia and pharmaceutical companies.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Receptores sigma/efeitos dos fármacos , Animais , Desenho de Fármacos , Humanos , Ligantes , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Neoplasias/patologia , Patentes como Assunto , Receptores sigma/metabolismo
17.
Handb Exp Pharmacol ; 244: 177-218, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28110353

RESUMO

Sigma receptors (σRs) are structurally unique proteins that function intracellularly as chaperones. Historically, σRs have been implicated as modulators of psychomotor stimulant effects and have at times been proposed as potential avenues for modifying stimulant abuse. However, the influence of ligands for σRs on the effects of stimulants, such as cocaine or methamphetamine, in various preclinical procedures related to drug abuse has been varied. The present paper reviews the effects of σR agonists and antagonists in three particularly relevant procedures: stimulant discrimination, place conditioning, and self-administration. The literature to date suggests limited σR involvement in the discriminative-stimulus effects of psychomotor stimulants, either with σR agonists substituting for the stimulant or with σR antagonists blocking stimulant effects. In contrast, studies of place conditioning suggest that administration of σR antagonists or down-regulation of σR protein can block the place conditioning induced by stimulants. Despite place conditioning results, selective σR antagonists are inactive in blocking the self-administration of stimulants. However, compounds binding to the dopamine transporter and blocking σRs can selectively decrease stimulant self-administration. Further, after self-administration of stimulants, σR agonists are self-administered, an effect not seen in subjects without that specific history. These findings suggest that stimulants induce unique changes in σR activity, and once established, the changes induced create redundant, and dopamine independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of those pathways, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse.


Assuntos
Comportamento Aditivo/psicologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Sistema Nervoso Central/efeitos dos fármacos , Usuários de Drogas/psicologia , Receptores sigma/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/psicologia , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Discriminação Psicológica/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Receptores sigma/metabolismo , Reforço Psicológico , Autoadministração , Transdução de Sinais , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
18.
Handb Exp Pharmacol ; 244: 219-236, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28039543

RESUMO

Although extensive research has focused on understanding the neurobiological mechanisms underlying alcohol addiction, pharmacological treatments for alcohol use disorders are very limited and not always effective. This constraint has encouraged the search for novel pharmacological targets for alcoholism therapy. Sigma receptors were shown to mediate some of the properties of cocaine and amphetamine, which was attributed to the direct binding of psychostimulants to these receptors. More recently, the role of sigma receptors in the rewarding and reinforcing effects of alcohol was also proposed, and it was suggested that their hyperactivity may result in excessive alcohol drinking. This chapter reviews current knowledge on the topic, and suggests that the sigma receptor system may represent a new therapeutic target for the treatment of alcohol use disorders.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Transtornos Relacionados ao Uso de Álcool/metabolismo , Bebidas Alcoólicas/efeitos adversos , Depressores do Sistema Nervoso Central/efeitos adversos , Sistema Nervoso Central/efeitos dos fármacos , Etanol/efeitos adversos , Receptores sigma/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Comportamento de Procura de Droga , Humanos , Locomoção/efeitos dos fármacos , Receptores sigma/metabolismo , Recompensa , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia
19.
Pharmacol Biochem Behav ; 150-151: 198-206, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27851908

RESUMO

This study examined the effect of the N-phenylpropyl-N'-substituted piperazine ligands SA4503 (3.4-dimethoxyphenethyl), YZ-067 (4-methoxyphenethyl), YZ-185 (3-methoxyphenethyl) and Nahas-3h (4-methoxybenzyl) on methamphetamine-induced hyperactivity in mice. In a previous study in rats, SA4503 increased methamphetamine-induced hyperactivity at a lower ligand dose and enhanced it at a higher dose. The other ligands have not been investigated in this assay. Presently, mice were administered sigma ligands, and specific [125I]E-IA-DM-PE-PIPZE and [125I]RTI-121 binding was measured to determine σ1 sigma receptor and dopamine transporter occupancy, respectively. Mice were also administered sigma ligands followed by methamphetamine, and locomotor activity was measured. Each of the ligands occupied σ1 sigma receptors (ED50=0.2-0.6µmol/kg) with similar potency, but none occupied the transporter (ED50>10µmol/kg). At the highest dose tested (31.6µmol/kg) all four sigma ligands significantly attenuated methamphetamine-induced hyperactivity. Interestingly, SA4503, YZ-067 and Nahas-3h, but not YZ-185, enhanced methamphetamine-induced hyperactivity at lower ligand doses (1-3.16µmol/kg). These results suggest that these ligands function as stimulant agonists at lower doses and as antagonists at higher does, with subtle changes in the substitution pattern at the 3- and 4-positions of the phenethyl group contributing to the nature of the interactions. Overall, these data indicate a complex role for σ1 sigma receptor ligands in methamphetamine's behavioral effects.


Assuntos
Hipercinese/induzido quimicamente , Metanfetamina/farmacologia , Piperazinas/farmacologia , Receptores sigma/efeitos dos fármacos , Animais , Cocaína/análogos & derivados , Cocaína/metabolismo , Masculino , Camundongos , Receptores sigma/agonistas , Receptores sigma/fisiologia , Relação Estrutura-Atividade
20.
Pharmazie ; 71(3): 146-51, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27183709

RESUMO

Two novel 8-azabicyclo[3.2.1]octan-3-ol derivatives, 11a and 11b, with high affinity for sigma-2 receptors and a very good sigma-1/sigma-2 selectivity ratio were synthesized. In comparison with several well established sigma-2 selective ligands, 11 b showed a very low sigma-1 receptor affinity. Functional assays demonstrated that 11b acts as an agonist and in A-375 human melanoma cell line is able to lower levels of procaspase-3, thus confirming a potential major role for sigma-2 pure agonists in the treatment of rapid proliferating melanoma cells.


Assuntos
Caspase 3/metabolismo , Melanoma Experimental/enzimologia , Receptores sigma/efeitos dos fármacos , Animais , Caspase 3/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Cobaias , Humanos , Íleo/efeitos dos fármacos , Técnicas In Vitro , Melanoma Experimental/tratamento farmacológico , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Especificidade por Substrato
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