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Sigma 1 agonist

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https://www.readbyqxmd.com/read/28315279/the-role-of-sigma-1-receptor-as-a-neuroprotective-target-in-glaucoma
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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...
February 8, 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
#7
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
#8
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
#9
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
https://www.readbyqxmd.com/read/28063892/an-intraocular-drug-delivery-system-using-targeted-nanocarriers-attenuates-retinal-ganglion-cell-degeneration
#10
Lei Zhao, Guojun Chen, Jun Li, Yingmei Fu, Timur A Mavlyutov, Annie Yao, Robert W Nickells, Shaoqin Gong, Lian-Wang Guo
Glaucoma is a common blinding disease characterized by loss of retinal ganglion cells (RGCs). To date, there is no clinically available treatment directly targeting RGCs. We aim to develop an RGC-targeted intraocular drug delivery system using unimolecular micelle nanoparticles (unimNPs) to prevent RGC loss. The unimNPs were formed by single/individual multi-arm star amphiphilic block copolymer poly(amidoamine)-polyvalerolactone-poly(ethylene glycol) (PAMAM-PVL-PEG). While the hydrophobic PAMAM-PVL core can encapsulate hydrophobic drugs, the hydrophilic PEG shell provides excellent water dispersity...
February 10, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/27986591/spinal-d-serine-increases-pkc-dependent-glun1-phosphorylation-contributing-to-the-sigma-1-receptor-induced-development-of-mechanical-allodynia-in-a-mouse-model-of-neuropathic-pain
#11
Sheu-Ran Choi, Ji-Young Moon, Dae-Hyun Roh, Seo-Yeon Yoon, Soon-Gu Kwon, Hoon-Seong Choi, Suk-Yun Kang, Ho-Jae Han, Alvin J Beitz, Jang-Hern Lee
We have recently demonstrated that spinal sigma-1 receptor (Sig-1R) activation facilitates nociception via an increase in phosphorylation of the NMDA receptor GluN1 subunit (pGluN1). The present study was designed to examine whether the Sig-1R-induced facilitative effect on NMDA-induced nociception is mediated by D-serine, and whether D-serine modulates spinal pGluN1 expression and the development of neuropathic pain following chronic constriction injury (CCI) of the sciatic nerve. Intrathecal administration of the D-serine degrading enzyme, DAAO attenuated the facilitation of NMDA-induced nociception induced by the Sig-1R agonist, PRE084...
December 13, 2016: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/27886264/sigma-1-receptor-agonism-promotes-mechanical-allodynia-after-priming-the-nociceptive-system-with-capsaicin
#12
J M Entrena, C Sánchez-Fernández, F R Nieto, R González-Cano, S Yeste, E J Cobos, J M Baeyens
Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions...
November 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27851908/n-phenylpropyl-n-substituted-piperazines-occupy-sigma-receptors-and-alter-methamphetamine-induced-hyperactivity-in-mice
#13
Dennis K Miller, Eric S Park, Susan Z Lever, John R Lever
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 [(125)I]E-IA-DM-PE-PIPZE and [(125)I]RTI-121 binding was measured to determine σ1 sigma receptor and dopamine transporter occupancy, respectively...
November 2016: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/27818324/the-sigma-1-receptor-mediates-the-beneficial-effects-of-pridopidine-in-a-mouse-model-of-huntington-disease
#14
Daniel Ryskamp, Jun Wu, Michal Geva, Rebecca Kusko, Iris Grossman, Michael Hayden, Ilya Bezprozvanny
The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated "dopamine stabilizer", has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD...
January 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/27601184/neuronal-nos-activates-spinal-nadph-oxidase-2-contributing-to-central-sigma-1-receptor-induced-pain-hypersensitivity-in-mice
#15
Sheu-Ran Choi, Soon-Gu Kwon, Hoon-Seong Choi, Ho-Jae Han, Alvin James Beitz, Jang-Hern Lee
We recently demonstrated that activation of spinal sigma-1 receptors (Sig-1Rs) induces pain hypersensitivity via the activation of neuronal nitric oxide synthase (nNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2). However, the potential direct interaction between nNOS-derived nitric oxide (NO) and Nox2-derived reactive oxygen species (ROS) is poorly understood, particularly with respect to the potentiation of N-methyl-D-aspartate (NMDA) receptor activity in the spinal cord associated with the development of central sensitization...
December 1, 2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27555879/4-aroylpiperidines-and-4-%C3%AE-hydroxyphenyl-piperidines-as-selective-sigma-1-receptor-ligands-synthesis-preliminary-pharmacological-evaluation-and-computational-studies
#16
Hermia N Ikome, Fidele Ntie-Kang, Moses N Ngemenya, Zhude Tu, Robert H Mach, Simon M N Efange
BACKGROUND: Sigma (σ) receptors are membrane-bound proteins characterised by an unusual promiscuous ability to bind a wide variety of drugs and their high affinity for typical neuroleptic drugs, such as haloperidol, and their potential as alternative targets for antipsychotic agents. Sigma receptors display diverse biological activities and represent potential fruitful targets for therapeutic development in combating many human diseases. Therefore, they present an interesting avenue for further exploration...
2016: Chemistry Central Journal
https://www.readbyqxmd.com/read/27397487/the-effect-of-the-sigma-1-receptor-selective-compound-ls-1-137-on-the-doi-induced-head-twitch-response-in-mice
#17
Maninder Malik, Claudia Rangel-Barajas, Robert H Mach, Robert R Luedtke
Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined...
September 2016: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/27366902/computer-assisted-design-synthesis-binding-and-cytotoxicity-assessments-of-new-1-4-aryl-methyl-amino-butyl-heterocyclic-sigma-1-ligands
#18
Daniele Zampieri, Luciano Vio, Maurizio Fermeglia, Sabrina Pricl, Bernhard Wünsch, Dirk Schepmann, Maurizio Romano, Maria Grazia Mamolo, Erik Laurini
In this work we applied a blend of computational and synthetic techniques with the aim to design, synthesize, and characterize new σ1 receptor (σ1R) ligands. Starting from the structure of previously reported, high-affinity benzoxazolone-based σ1 ligands, the three-dimensional homology model of the σ1R was exploited for retrieving the molecular determinants to fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by other heterocyclic scaffolds, the relevant conformational space in the σ1R binding cavity was explored, and the effect on σ1R binding affinity was ultimately assessed...
October 4, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27262426/new-bifunctional-antioxidant-%C3%AF-1-agonist-ligands-preliminary-chemico-physical-and-biological-evaluation
#19
Emanuela Arena, Ivana Cacciatore, Laura S Cerasa, Hasan Turkez, Valeria Pittalà, Lorella Pasquinucci, Agostino Marrazzo, Carmela Parenti, Antonio Di Stefano, Orazio Prezzavento
We previously reported bifunctional sigma-1 (σ1) ligands endowed with antioxidant activity (1 and 2). In the present paper, pure enantiomers (R)-1 and (R)-2 along with the corresponding p-methoxy (6, 11), p-fluoro derivatives (7, 12) were synthesized. σ1 and σ2 affinities, antioxidant properties, and chemico-physical profiles were evaluated. Para derivatives, while maintaining strong σ1 affinity, displayed improved σ1 selectivity compared to the parent compounds 1 and 2. In vivo evaluation of compounds 1, 2, (R)-1, 7, and 12 showed σ1 agonist pharmacological profile...
July 15, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27245248/pimavanserin-an-inverse-agonist-antipsychotic-drug
#20
Robert H Howland
Approximately all clinically useful antipsychotic drugs have known activity as dopamine receptor antagonists, but many of these drugs also are inverse agonists at the serotonin-2A (5HT2A) receptor. Pimavanserin is an inverse agonist at the 5HT2A receptor, with a lower binding affinity at the serotonin-2C receptor and sigma 1 receptor, but no significant binding to dopamine or other receptors. Because of its unique pharmacology, pimavanserin was approved for the treatment of psychosis associated with Parkinson's disease, and it has a low risk for exacerbating motor symptoms compared to standard antipsychotic medications...
June 1, 2016: Journal of Psychosocial Nursing and Mental Health Services
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