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https://www.readbyqxmd.com/read/29458169/inhibition-of-microsomal-prostaglandin-e-synthase-1-facilitates-liver-repair-after-hepatic-injury-in-mice
#1
Nobuyuki Nishizawa, Yoshiya Ito, Koji Eshima, Hirotoki Ohkubo, Ken Kojo, Tomoyoshi Inoue, Joan Raouf, Per-Johan Jakobsson, Satoshi Uematsu, Shizuo Akira, Shuh Narumiya, Masahiko Watanabe, Masataka Majima
BACKGROUND & AIMS: Liver repair following hepatic ischemia/reperfusion (I/R) injury is crucial to survival. This study aims to examine the role of endogenous prostaglandin E2 (PGE2 ) produced by inducible microsomal PGE synthase-1 (mPGES-1), a terminal enzyme of PGE2 generation, in liver injury and repair following hepatic I/R. METHODS: mPGES-1 deficient (mPGES-1-/- ) mice or their wild counterparts (WT) were subjected to partial hepatic ischemia followed by reperfusion...
February 16, 2018: Journal of Hepatology
https://www.readbyqxmd.com/read/29458074/subthalamic-nucleus-stimulation-dopaminergic-treatment-and-impulsivity-in-parkinson-s-disease
#2
Frédérique Fluchère, Borís Burle, Franck Vidal, Wery van den Wildenberg, Tatiana Witjas, Alexandre Eusebio, Jean-Philippe Azulay, Thierry Hasbroucq
BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN DBS) is known to increase response speed and lower response accuracy in Parkinson's disease (PD) patients. It has been proposed that this speed-accuracy tradeoff is due to enhanced sensitivity of the motor system to sensory information. An alternative possibility is that this effect is due to weakened suppressive processes. The two alternative interpretations can be tested by analyzing the electromyographic activity (EMG) of the response agonists when the patients perform conflict reaction time tasks...
February 16, 2018: Neuropsychologia
https://www.readbyqxmd.com/read/29456505/deletion-of-trace-amine-associated-receptor-1-attenuates-behavioral-responses-to-caffeine
#3
Michael D Schwartz, Jeremiah B Palmerston, Diana L Lee, Marius C Hoener, Thomas S Kilduff
Trace amines (TAs), endogenous amino acid metabolites that are structurally similar to the biogenic amines, are endogenous ligands for trace amine-associated receptor 1 (TAAR1), a GPCR that modulates dopaminergic, serotonergic, and glutamatergic activity. Selective TAAR1 full and partial agonists exhibit similar pro-cognitive, antidepressant- and antipsychotic-like properties in rodents and non-human primates, suggesting TAAR1 as a novel target for the treatment of neurological and psychiatric disorders. We previously reported that TAAR1 partial agonists are wake-promoting in rats and mice, and that TAAR1 knockout (KO) and overexpressing mice exhibit altered sleep-wake and EEG spectral composition...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29456112/discovery-of-dsp-1053-a-novel-benzylpiperidine-derivative-with-potent-serotonin-transporter-inhibitory-activity-and-partial-5-ht-1a-receptor-agonistic-activity
#4
Hidefumi Yoshinaga, Tomoaki Nishida, Izumi Sasaki, Taro Kato, Hitomi Oki, Kazuki Yabuuchi, Tomohiro Toyoda
We have previously shown that SMP-304, a serotonin uptake inhibitor with weak 5-HT1A partial agonistic activity, may act under high serotonin levels as a 5-HT1A antagonist that improves the onset of paroxetine in the rat swimming test. However, SMP-304 is mostly metabolized by CYP2D6, indicating limited efficacy among individuals and increased side effects. To reduce CYP2D6 metabolic contribution and enhance SERT/5-HT1A binding affinity, we carried out a series of substitutions at the bromine atom in the left part of the benzene ring of SMP-304 and replaced the right part of SMP-304 with a chroman-4-one...
February 8, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29455292/effects-of-the-nicotinic-agonist-varenicline-nicotinic-antagonist-r-bpidi-and-dat-inhibitor-r-modafinil-on-co-use-of-ethanol-and-nicotine-in-female-p-rats
#5
Sarah E Maggio, Meredith A Saunders, Thomas A Baxter, Kimberly Nixon, Mark A Prendergast, Guangrong Zheng, Peter Crooks, Linda P Dwoskin, Rachel D Slack, Amy H Newman, Richard L Bell, Michael T Bardo
RATIONALE: Co-users of alcohol and nicotine are the largest group of polysubstance users worldwide. Commonalities in mechanisms of action for ethanol (EtOH) and nicotine proposes the possibility of developing a single pharmacotherapeutic to treat co-use. OBJECTIVES: Toward developing a preclinical model of co-use, female alcohol-preferring (P) rats were trained for voluntary EtOH drinking and i.v. nicotine self-administration in three phases: (1) EtOH alone (0 vs...
February 18, 2018: Psychopharmacology
https://www.readbyqxmd.com/read/29453925/impact-of-opioid-therapy-on-gonadal-hormones-focus-on-buprenorphine
#6
REVIEW
Anjali Varma, Mamta Sapra, Ali Iranmanesh
Objective The USA is in the midst of an opioid crisis. Understanding the impact of opioids and commonly used treatments for opioid dependence is essential for clinicians and researchers in order to educate and treat the nation's growing population with opioid use disorders. As a relatively new treatment for opioid dependence, buprenorphine is gaining popularity to the extent of becoming not only a preferred approach to the maintenance of opiate addiction, but also an option for chronic pain management. The purpose of this report is to review the available evidence on the endocrine effects of buprenorphine, particularly as it relates to the hypothalamic-pituitary-gonadal (HPG) axis, which is controversial and not fully defined...
February 17, 2018: Hormone Molecular Biology and Clinical Investigation
https://www.readbyqxmd.com/read/29453736/reproductive-epidemiology-of-glial-tumors-may-reveal-novel-treatments-high-dose-progestins-or-progesterone-antagonists-as-endocrino-immune-modifiers-against-glioma
#7
REVIEW
Meric A Altinoz, Aysel Ozpinar, Ilhan Elmaci
Female gender, contraceptives, and menopausal hormone replacement treatments containing progesterone analogues associate with higher risk of meningiomas yet with lower risk of gliomas. Progesterone receptor (PR) expression and mifepristone treatment was highly discussed for meningiomas. However, much less is known in regard to progesterone actions in gliomas despite PR expression strongly correlates with their grade. Meningiomas and gliomas may grow faster during gestation; but paradoxically, parousity reduces lifetime risk of gliomas which can be explained with dichotomous cell growth-stimulating and inhibitory actions of progesterone at low versus high levels...
February 17, 2018: Neurosurgical Review
https://www.readbyqxmd.com/read/29453462/gq-11-a-new-ppar-agonist-improves-obesity-induced-metabolic-alterations-in-ldlr-mice
#8
Jacqueline C Silva, Edson M de Oliveira, Walter M Turato, Gustavo H G Trossini, Vinícius G Maltarollo, Marina G R Pitta, Ivan R Pitta, Beatriz de Las Heras, Lisardo Boscá, Martina Rudnicki, Dulcineia S P Abdalla
BACKGROUND: Obesity and insulin resistance/diabetes are important risk factors for cardiovascular diseases and demand safe and efficacious therapeutics. OBJECTIVE: To assess the effects of a new thiazolidine compound-GQ-11-on obesity and insulin resistance induced by a diabetogenic diet in LDL receptor-deficient (LDLr -/- ) mice. METHODS: Molecular docking simulations of GQ-11, PPARα and PPARγ structures were performed. Male C57BL/6J LDLr -/- mice fed a diabetogenic diet for 24 weeks were treated with vehicle, GQ-11 or pioglitazone or (20 mg/kg/day) for 28 days by oral gavage...
January 30, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/29451794/-s-2-amino-3-5-methyl-3-hydroxyisoxazol-4-yl-propanoic-acid-ampa-and-kainate-receptor-ligands-further-exploration-of-bioisosteric-replacements-structural-and-biological-investigation
#9
Simone Brogi, Margherita Brindisi, Stefania Butini, Giridhar Uttam Kshirsagar, Samuele Maramai, Giulia Chemi, Sandra Gemma, Giuseppe Campiani, Ettore Novellino, Paolo Fiorenzani, Jessica Pinassi, Anna Maria Aloisi, Mikko Gynther, Raminta Venskutonyte, Liwei Han, Karla Frydenvang, Jette Sandholm Kastrup, Darryl S Pickering
Starting from 1-4 and 7 structural templates, analogues based on bioisosteric replacements (5a-c vs 1, 2 and 6 vs 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1 and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated determining the X-ray structures of the GluK3-LBD with 2 and 5c and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).
February 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29449830/screening-for-ppar-non-agonist-ligands-followed-by-characterization-of-a-hit-am-879-with-additional-no-adipogenic-and-cdk5-mediated-phosphorylation-inhibition-properties
#10
Helder Veras Ribeiro Filho, Natália Bernardi Videira, Aline Villanova Bridi, Thais Helena Tittanegro, Fernanda Aparecida Helena Batista, José Geraldo de Carvalho Pereira, Paulo Sérgio Lopes de Oliveira, Marcio Chaim Bajgelman, Albane Le Maire, Ana Carolina Migliorini Figueira
Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor, playing key roles in maintenance of adipose tissue and in regulation of glucose and lipid homeostasis. This receptor is the target of thiazolidinediones, a class of antidiabetic drugs, which improve insulin sensitization and regulate glycemia in type 2 diabetes. Despite the beneficial effects of drugs, such as rosiglitazone and pioglitazone, their use is associated with several side effects, including weight gain, heart failure, and liver disease, since these drugs induce full activation of the receptor...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29449556/cd1d-dependent-immune-suppression-mediated-by-regulatory-b-cells-through-modulations-of-inkt-cells
#11
K Oleinika, E C Rosser, D E Matei, K Nistala, A Bosma, I Drozdov, C Mauri
Regulatory B cells (Breg) express high levels of CD1d that presents lipid antigens to invariant natural killer T (iNKT) cells. The function of CD1d in Breg biology and iNKT cell activity during inflammation remains unclear. Here we show, using chimeric mice, cell depletion and adoptive cell transfer, that CD1d-lipid presentation by Bregs induces iNKT cells to secrete interferon (IFN)-γ to contribute, partially, to the downregulation of T helper (Th)1 and Th17-adaptive immune responses and ameliorate experimental arthritis...
February 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29447132/role-of-gpcr-mu-opioid-receptor-tyrosine-kinase-epidermal-growth-factor-crosstalk-in-opioid-induced-hyperalgesic-priming-type-ii
#12
Dionéia Araldi, Luiz F Ferrari, Jon D Levine
Repeated stimulation of mu-opioid receptors (MORs), by an MOR-selective agonist DAMGO induces type II priming, a form of nociceptor neuroplasticity, which has 2 components: opioid-induced hyperalgesia (OIH) and prolongation of prostaglandin-E2 (PGE2)-induced hyperalgesia. We report that intrathecal antisense knockdown of the MOR in nociceptors, prevented the induction of both components of type II priming. Type II priming was also eliminated by SSP-saporin, which destroys the peptidergic class of nociceptors...
January 11, 2018: Pain
https://www.readbyqxmd.com/read/29446699/investigating-d-cycloserine-as-a-potential-pharmacological-enhancer-of-an-emotional-bias-learning-procedure
#13
Marcella L Woud, Simon E Blackwell, Susann Steudte-Schmiedgen, Michael Browning, Emily A Holmes, Catherine J Harmer, Jürgen Margraf, Andrea Reinecke
The partial N-methyl-D-aspartate receptor agonist d-cycloserine may enhance psychological therapies. However, its exact mechanism of action is still being investigated. Cognitive bias modification techniques allow isolation of cognitive processes and thus investigation of how they may be affected by d-cycloserine. We used a cognitive bias modification paradigm targeting appraisals of a stressful event, Cognitive Bias Modification-Appraisal, to investigate whether d-cycloserine enhanced the modification of appraisal, and whether it caused greater reduction in indices of psychopathology...
February 1, 2018: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/29444937/maraviroc-is-associated-with-latent-hiv-1-reactivation-through-nf-%C3%AE%C2%BAb-activation-in-resting-cd4-t-cells-from-hiv-infected-individuals-on-suppressive-antiretroviral-therapy
#14
Nadia Madrid-Elena, María Laura García-Bermejo, Sergio Serrano-Villar, Alberto Díaz-de Santiago, Beatriz Sastre, Carolina Gutiérrez, Fernando Dronda, María Coronel Díaz, Ester Domínguez, María Rosa López-Huertas, Beatriz Hernández-Novoa, Santiago Moreno
Maraviroc is a CCR5 antagonist used in the treatment of HIV-1 infection. We and others have suggested that maraviroc could reactivate latent HIV-1. To test the latency reversing potential of maraviroc and the mechanisms involved, we performed a phase-II, single-center, open-label study in which maraviroc was administered for 10 days to 20 HIV-1-infected individuals on suppressive antiretroviral therapy (Eudra CT: 2012-003215-66). All patients completed full maraviroc dosing and follow up. The primary endpoint was to study whether maraviroc may reactivate HIV-1 latency, eliciting signalling pathways involved in the viral reactivation...
February 14, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29437248/mechanism-of-agonism-and-antagonism-of-the-pseudomonas-aeruginosa-quorum-sensing-regulator-qscr-with-non-native-ligands
#15
Christina L Wysoczynski-Horita, Michelle E Boursier, Ryan Hill, Kirk Hansen, Helen E Blackwell, Mair E A Churchill
Pseudomonas aeruginosa is an opportunistic pathogen that uses the process of quorum sensing (QS) to coordinate the expression of many virulence genes. During quorum sensing, N-acyl-homoserine lactone (AHL) signaling molecules regulate the activity of three LuxR-type transcription factors, LasR, RhlR, and QscR. To better understand P. aeruginosa QS signal reception, we examined the mechanism underlying the response of QscR to synthetic agonists and antagonists using biophysical and structural approaches. The structure of QscR bound to a synthetic agonist reveals a novel mode of ligand binding supporting a general mechanism for agonist activity...
February 13, 2018: Molecular Microbiology
https://www.readbyqxmd.com/read/29436395/myeloid-targeted-immunotherapies-act-in-synergy-to-induce-inflammation-and-antitumor-immunity
#16
Curtis J Perry, Andrés R Muñoz-Rojas, Katrina M Meeth, Laura N Kellman, Robert A Amezquita, Durga Thakral, Victor Y Du, Jake Xiao Wang, William Damsky, Alexandra L Kuhlmann, Joel W Sher, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech
Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state...
February 7, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29434492/sr-16234-a-novel-selective-estrogen-receptor-modulator-for-pain-symptoms-with-endometriosis-an-open-label-clinical-trial
#17
Tasuku Harada, Ikuko Ohta, Yusuke Endo, Hiroshi Sunada, Hisashi Noma, Fuminori Taniguchi
Background: SR-16234 is a selective estrogen receptor modulator (SERM) structurally different from approved SERM and has been reported to have estrogen receptor (ER) α antagonistic activity and strong affinity with a weak partial agonistic activity to ERβ receptor. SR-16234 showed strong inhibitory effects on transplanted endometrial cysts in the endometriosis model of rat and mouse. In this clinical trial, efficacy and safety of SR-16234 have been evaluated in endometriosis patients...
December 2017: Yonago Acta Medica
https://www.readbyqxmd.com/read/29433907/in%C3%A2-vitro-nuclear-receptor-inhibition-and-cytotoxicity-of-hydraulic-fracturing-chemicals-and-their-binary-mixtures
#18
Peter A Bain, Anu Kumar
The widespread use of hydraulic fracturing (HF) in oil and gas extraction operations has led to concern over environmental risks posed by chemicals used in HF fluids. Here we employed a suite of stable luciferase reporter gene assays to investigate the potential for selected HF chemicals or geogenics to activate or antagonise nuclear receptor signalling. We screened three biocides (bronopol [BP], glutaraldehyde [GA], and tetrakis(hydroxymethyl)phosphonium sulfate [THPS]), a surfactant (2-butoxyethanol), a friction reducer (polyacrylamide), and a coal seam geogenic (o-cresol) for their potential to act as agonists or antagonists of the estrogen receptor, androgen receptor, progesterone receptor (PR), glucocorticoid receptor or peroxisome proliferator-activated receptor gamma (PPARγ)...
January 9, 2018: Chemosphere
https://www.readbyqxmd.com/read/29433092/structure-based-optimization-of-free-fatty-acid-receptor-1-agonists-bearing-thiazole-scaffold
#19
Zheng Li, Xue Xu, Jie Hou, Shaohong Wang, Hongwei Jiang, Luyong Zhang
The free fatty acid receptor 1 (FFA1) plays an important role in amplifying insulin secretion in a glucose dependent manner. We have previously reported a series of FFA1 agonists with thiazole scaffold exemplified by compound 1, and identified a small hydrophobic subpocket partially occupied by the methyl group of compound 1. Herein, we describe further structure optimization to better fit the small hydrophobic subpocket by replacing the small methyl group with other hydrophobic substituents. All of these efforts resulted in the identification of compound 6, a potent FFA1 agonist (EC 50 = 39...
February 1, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29432796/opioid-and-%C3%AE-2-adrenergic-mechanisms-are-activated-by-gaba-agonists-in-the-lateral-parabrachial-nucleus-to-induce-sodium-intake
#20
Lisandra B De Oliveira, Carina A F Andrade, Laurival A De Luca, Débora S A Colombari, José V Menani
The activation of GABA, opioid or α 2 adrenergic mechanisms in the lateral parabrachial nucleus (LPBN) facilitates hypertonic NaCl intake in rats. In the present study, we combined opioid or α 2 adrenergic antagonists with GABA agonists into the LPBN in order to investigate if NaCl intake caused by GABAergic activation in normohydrated rats depends on opioid or α 2 -adrenergic mechanisms in this area. Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN were used. Bilateral injections of muscimol or baclofen (GABA A and GABA B agonists, respectively, 0...
February 9, 2018: Brain Research Bulletin
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