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Sigma 1 agonist

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https://www.readbyqxmd.com/read/28644012/sigma-2-receptor-tmem97-agonists-produce-long-lasting-anti-neuropathic-pain-effects-in-mice
#1
James J Sahn, Galo L Mejia, Pradipta R Ray, Stephen F Martin, Theodore John Price
Neuropathic pain is an important medical problem with few effective treatments. The sigma 1 receptor (σ1R) is a potential target for neuropathic pain therapeutics, and antagonists for this receptor are effective in preclinical models and are currently in phase II clinical trials. Relatively little is known about the σ2R, which has recently been identified as transmembrane protein 97 (Tmem97). We generated a series of σ1R and σ2R/Tmem97 agonists and antagonists and tested them for efficacy in the mouse spared nerve injury (SNI) model...
June 23, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28603497/sigma-1-receptor-plays-a-negative-modulation-on-n-type-calcium-channel
#2
Kang Zhang, Zhe Zhao, Liting Lan, Xiaoli Wei, Liyun Wang, Xiaoyan Liu, Haitao Yan, Jianquan Zheng
The sigma-1 receptor is a 223 amino acids molecular chaperone with a single transmembrane domain. It is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes. By chaperone-mediated interactions with ion channels, G-protein coupled receptors and cell-signaling molecules, the sigma-1 receptor performs broad physiological and pharmacological functions. Despite sigma-1 receptors have been confirmed to regulate various types of ion channels, the relationship between the sigma-1 receptor and N-type Ca(2+) channel is still unclear...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28554311/the-role-of-sigma-1-receptor-an-intracellular-chaperone-in-neurodegenerative-diseases
#3
Botond Penke, Lívia Fülöp, Mária Szűcs, Ede Frecska
Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death. ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM...
May 28, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28549090/sigma-1-receptor-regulates-mitochondrial-function-in-glucose-and-oxygen-deprived-retinal-ganglion-cells
#4
Dorette Z Ellis, Linya Li, Yong Park, Shaoqing He, Brett Mueller, Thomas Yorio
Purpose: Understanding the role of mitochondria in retinal ganglion cells (RGCs) is relevant to human disease as studies have shown mitochondrial abnormalities in primary open-angle glaucoma patients. This study seeks to determine the effects of the sigma-1 receptor (σ-1r) and its agonists on mitochondrial function in oxygen- and glucose- deprived (OGD) purified neonatal RGCs. Methods: Retinal ganglion cells were isolated from rat pups and subjected to OGD in varying conditions in the presence or absence of σ-1r agonist and antagonist and following addition of an AAV2-σ-1r vector that was used to increase σ-1r expression...
May 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28495886/the-sigma-1-receptor-modulates-dopamine-transporter-conformation-and-cocaine-binding-and-may-thereby-potentiate-cocaine-self-administration-in-rats
#5
Weimin Conrad Hong, Hideaki Yano, Takato Hiranita, Frederick T Chin, Christopher R McCurdy, Tsung-Ping Su, Susan G Amara, Jonathan L Katz
The dopamine transporter (DAT) regulates dopamine (DA) neurotransmission by recapturing DA into the presynaptic terminals, and is a principal target of the psychostimulant cocaine. The sigma-1 receptor (σ1R) is a molecular chaperone, and its ligands have been shown to modulate dopamine neuronal signaling, although their effects on DAT activity are unclear. Here, we report that the prototypical σ1R agonist (+)-pentazocine potentiated the dose response of cocaine self-administration in rats, consistent with effects of the σR agonists PRE-084 and DTG reported previously...
May 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28455697/the-differentiation-of-skin-mesenchymal-stem-cells-towards-a-schwann-cell-phenotype-impact-of-sigma-1-receptor-activation
#6
L Saulite, E Vavers, L Zvejniece, M Dambrova, U Riekstina
Neural crest stem cells (NCSCs) are the source of mature Schwann cells in the peripheral nervous system (PNS). The NCSC population resides in the bulge of hair follicles and in the dermis. Recently, it was shown that 2-3% of the human dermis mesenchymal stem cell (MSC) population expresses the NCSC marker CD271, thus enabling the use of skin MSCs for studying Schwann cell differentiation in vitro. The aims of this study were to establish a protocol for human skin MSC differentiation towards Schwann cell-like cells (SC-lcs) and to analyse the expression of sigma-1 receptor (S1R) in SC-lcs...
April 28, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28442581/%C3%AF-receptor-effects-of-n-substituted-benztropine-analogs-implications-for-antagonism-of-cocaine-self-administration
#7
Takato Hiranita, Weimin C Hong, Theresa Kopajtic, Jonathan L Katz
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...
July 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28431607/sigma-1-receptor-in-brain-ischemia-reperfusion-possible-role-in-the-nr2a-induced-pathway-to-regulate-brain-derived-neurotrophic-factor
#8
Qian Xu, Xue-Fei Ji, Tian-Yan Chi, Peng Liu, Ge Jin, Ling Chen, Li-Bo Zou
Sigma-1 receptor (σ1r) activation could attenuate the learning and memory deficits in the AD model, ischemia model and others. In our previous study, the activation of σ1r increased the expression of brain-derived neurotrophic factor (BDNF), possibly through the NR2A-induced pathway, and σ1r agonists might function as neuroprotectant agents in vascular dementia. Here, we used σ1r knockout mice to confirm the role of σ1r. Furthermore, an antagonist of NR2A was first used to investigate whether the NR2A-induced pathway is the necessary link between σ1r and BDNF...
May 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28409931/1-4-18-f-fluorobenzyl-4-tetrahydrofuran-2-yl-methyl-piperazine-a-novel-suitable-radioligand-with-low-lipophilicity-for-imaging-%C3%AF-1-receptors-in-the-brain
#9
Yingfang He, Fang Xie, Jiajun Ye, Winnie Deuther-Conrad, Bixiao Cui, Liang Wang, Jie Lu, Jörg Steinbach, Peter Brust, Yiyun Huang, Jie Lu, Hongmei Jia
We have designed and synthesized novel piperazine compounds with low lipophilicity as σ1 receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ1 receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ2 receptors (52-fold), and adenosine A2A, adrenergic α2, cannabinoid CB1, dopamine D1, D2L, γ-aminobutyric acid A (GABAA), NMDA, melatonin MT1, MT2, and serotonin 5-HT1 receptors. The corresponding radiotracer [(18)F]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28389336/the-activity-of-selective-sigma-1-receptor-ligands-in-seizure-models-in-vivo
#10
Edijs Vavers, Baiba Svalbe, Lasma Lauberte, Ilmars Stonans, Ilga Misane, Maija Dambrova, Liga Zvejniece
Sigma-1 receptor (Sig1R) is a ligand-regulated protein which, since its discovery, has been widely studied as a novel target to treat neurological disorders, including seizures. However, the roles and mechanisms of Sig1R in the regulation of seizures are not fully understood. The aim of the present study was to test and compare effects of often used selective Sig1R ligands in models of experimentally induced seizures. The anti-seizure activities and interactions of selective Sig1R agonist PRE-084, selective Sig1R antagonist NE-100 and novel positive allosteric Sig1R modulator E1R were evaluated in pentylenetetrazol (PTZ) and (+)-bicuculline (BIC)-induced seizure models in mice...
April 4, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28370447/trial-of-dextromethorphan-quinidine-to-treat-levodopa-induced-dyskinesia-in-parkinson-s-disease
#11
Susan H Fox, Leonard Verhagen Metman, John G Nutt, Matthew Brodsky, Stewart A Factor, Anthony E Lang, Laura E Pope, Nadine Knowles, João Siffert
BACKGROUND: Nondopaminergic pathways represent potential targets to treat levodopa-induced dyskinesia in Parkinson's disease (PD). This pilot-study (NCT01767129) examined the safety/efficacy of the sigma-1 receptor-agonist and glutamatergic/monoaminergic modulator, dextromethorphan plus quinidine (to inhibit rapid dextromethorphan metabolism), for treating levodopa-induced dyskinesia. METHODS: PD patients were randomized to dextromethorphan/quinidine (45 mg/10 mg twice daily)/placebo in two 2-week double-blind, crossover treatment periods, with intervening 2-week washout...
March 30, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28315279/the-role-of-sigma-1-receptor-as-a-neuroprotective-target-in-glaucoma
#12
Barbara Mysona, Neil Kansara, Jing Zhao, Kathryn Bollinger
The role of sigma 1 receptor (S1R) in glaucoma is emerging as a promising field of study. Glaucoma is an optic neuropathy that shares common pathogenic mechanisms with other neurodegenerative diseases such as Alzheimer's and Parkinson's disease . S1R modulates multiple cellular functions associated with neurodegeneration . These include Ca(2+) ion homeostasis, endoplasmic reticulum (ER) and oxidative stress , survival signaling pathways, neurotrophin secretion, and glial activation. S1R may also have neurorestorative properties including enhancement of neuronal plasticity and neurite outgrowth...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28315276/the-sigma-1-receptor-a-therapeutic-target-for-the-treatment-of-als
#13
Timur A Mavlyutov, Erin M Baker, Tasher M Losenegger, Jaimie R Kim, Brian Torres, Miles L Epstein, Arnold E Ruoho
The membrane bound 223 amino acid Sigma-1 Receptor (S1R) serves as a molecular chaperone and functional regulator of many signaling proteins. Spinal cord motor neuron activation occurs, in part, via large ventral horn cholinergic synapses called C-boutons/C-terminals. Chronic excitation of motor neurons and alterations in C-terminals has been associated with Amyotrophic Lateral Sclerosis (ALS ). The S1R has an important role in regulating motor neuron function. High levels of the S1R are localized in postsynaptic endoplasmic reticulum (ER) subsurface cisternae within 10-20 nm of the plasma membrane that contain muscarinic type 2 acetylcholine receptors (M2AChR), calcium activated potassium channels (Kv2...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28315275/sigma-1-receptor-in-motoneuron-disease
#14
Renzo Mancuso, Xavier Navarro
Amyotrophic Lateral Sclerosis (ALS ) is a neurodegenerative disease affecting spinal cord and brain motoneurons , leading to paralysis and early death. Multiple etiopathogenic mechanisms appear to contribute in the development of ALS , including glutamate excitotoxicity, oxidative stress , protein misfolding, mitochondrial defects, impaired axonal transport, inflammation and glial cell alterations. The Sigma-1 receptor is highly expressed in motoneurons of the spinal cord, particularly enriched in the endoplasmic reticulum (ER) at postsynaptic cisternae of cholinergic C-terminals...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28315270/sigma-1-receptor-agonists-and-their-clinical-implications-in-neuropsychiatric-disorders
#15
Yakup Albayrak, Kenji Hashimoto
Accumulating evidence suggests that sigma-1 receptors play a role in the pathophysiology of neuropsychiatric diseases, as well as in the mechanisms of some selective serotonin reuptake inhibitors (SSRIs). Among the SSRIs, the order of affinity for sigma-1 receptors is as follows: fluvoxamine > sertraline > fluoxetine > escitalopram > citalopram > paroxetine. Some SSRIs (e.g., fluvoxamine, fluoxetine and escitalopram) and other drugs (donepezil , ifenprodil , dehydroepiandeterone (DHEA)) potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells, and these effects could be antagonized by the selective sigma-1 receptor antagonist NE-100...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28275911/sigma-1-%C3%AF-1-receptor-in-memory-and-neurodegenerative-diseases
#16
Tangui Maurice, Nino Goguadze
The sigma-1 (σ1) receptor has been associated with regulation of intracellular Ca(2+) 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...
March 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28188803/activation-of-the-sigma-1-receptor-by-haloperidol-metabolites-facilitates-brain-derived-neurotrophic-factor-secretion-from-human-astroglia
#17
Dhwanil A Dalwadi, Seongcheol Kim, John A Schetz
Glial cells play a critical role in neuronal support which includes the production and release of the neurotrophin brain-derived neurotrophic factor (BDNF). Activation of the sigma-1 receptor (S1R) has been shown to attenuate inflammatory stress-mediated brain injuries, and there is emerging evidence that this may involve a BDNF-dependent mechanism. In this report we studied S1R-mediated BDNF release from human astrocytic glial cells. Astrocytes express the S1R, which mediates BDNF release when stimulated with the prototypical S1R agonists 4-PPBP and (+)-SKF10047...
May 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28108357/sigma-1-receptor-deficiency-reduces-gabaergic-inhibition-in-the-basolateral-amygdala-leading-to-ltd-impairment-and-depressive-like-behaviors
#18
Baofeng Zhang, Ling Wang, Tingting Chen, Juan Hong, Sha Sha, Jun Wang, Hang Xiao, Ling Chen
Sigma-1 receptor knockout (σ1R(-/-)) in male mice causes depressive-like phenotype. We observed the expression of σ1R in principal neurons of basolateral amygdala (BLA), a main region for affective regulation. The present study investigated the influence of σ1R deficiency in BLA neurons on synaptic properties and plasticity at cortico-BLA pathway. In comparison with wild-type (WT) mice, the slopes of field excitatory postsynaptic potentials (fEPSP) were reduced in σ1R(-/-) mice with the increases in paired-pulse facilitation (PPF) and paired-pulse inhibition (PPI) values...
January 17, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28097006/contribution-of-sigma-1-receptor-to-cytoprotective-effect-of-afobazole
#19
Mikhail V Voronin, Ilya A Kadnikov
Anxiolytic afobazole (5-Ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihidrochloride) has pronounced ligand properties toward Sigma-1 receptor (σ1 receptor,SigmaR1) and MT 3 receptors. Our previous work demonstrated that afobazole possess cytoprotective effect in the in vitro model of menadione genotoxicity (Woods et al. 1997) through interaction with MT 3 receptor (Kadnikov et al. 2014). Present study utilized previously described models to address the contribution of SigmaR1 to cytoprotective action of afobazole...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28086830/sigma-2-receptor-agonist-derivatives-of-1-cyclohexyl-4-3-5-methoxy-1-2-3-4-tetrahydronaphthalen-1-yl-propyl-piperazine-pb28-induce-cell-death-via-mitochondrial-superoxide-production-and-caspase-activation-in-pancreatic-cancer
#20
Maria Laura Pati, John R Hornick, Mauro Niso, Francesco Berardi, Dirk Spitzer, Carmen Abate, William Hawkins
BACKGROUND: Despite considerable efforts by scientific research, pancreatic cancer is the fourth leading cause of cancer related mortalities. Sigma-2 receptors, which are overexpressed in several tumors, represent promising targets for triggering selective pancreatic cancer cells death. METHODS: We selected five differently structured high-affinity sigma-2 ligands (PB28, PB183, PB221, F281 and PB282) to study how they affect the viability of diverse pancreatic cancer cells (human cell lines BxPC3, AsPC1, Mia PaCa-2, and Panc1 and mouse Panc-02, KCKO and KP-02) and how this is reflected in vivo in a tumor model...
January 13, 2017: BMC Cancer
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