37,901 results match your criteria agonist binding


The High Affinity Dopamine D Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders.

ACS Chem Neurosci 2021 Apr 12. Epub 2021 Apr 12.

Division of Basic Neuroscience, Medicinal Chemistry Laboratory, McLean Hospital, Belmont, Massachusetts 02478, United States.

The dopamine D receptor exists in two different states, D and D; the former is the functional form of the D receptor and associates with intracellular G-proteins. The D agonist [H]MCL-536 has high affinity for the D receptor ( 0.8 nM) and potently displaces the binding of (-(-)---propylnorapomorphine (NPA; 0. Read More

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Polysaccharide Isolated From Activates TLR4 in Macrophage Cell Lines and Enhances Immune Responses in OVA-Immunized and LLC-Bearing Mouse Models.

Front Pharmacol 2021 24;12:609059. Epub 2021 Mar 24.

School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China.

Diels et Gilg is a valuable Chinese medicinal herb with a long history of clinical application. Our previous study isolated and characterized a purified polysaccharide from the aerial part of (SYQP) and found it having antipyretic and antitumor effects in mice. A preliminary mechanistic study suggests these effects may be related to the binding of toll-like receptor (TLR4). Read More

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Design and identification of a new farnesoid X receptor (FXR) partial agonist by computational structure-activity analysis: Ligand-induced H8 helix fluctuation in the ligand-binding domain of FXR may lead to partial agonism.

Bioorg Med Chem Lett 2021 Apr 8:128026. Epub 2021 Apr 8.

Graduate School of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima, 737-0112, Japan; Faculty of Clinical Nutrition, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima, 737-0112, Japan.

Farnesoid X receptor (FXR) controls gene-expression relevant to various diseases including nonalcoholic steatohepatitis and has become a drug target to regulate metabolic aberrations. However, some side effects of FXR agonists reported in clinical development such as an increase in blood cholesterol levels, incentivize the development of partial agonists to minimize side effects. In this study, to identify a new partial agonist, we analyzed the computational structure-activity relationship (SAR) of FXR agonists previously developed in our laboratories using molecular dynamics simulations. Read More

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Development of a chimeric vaccine candidate based on Toxoplasma gondii major surface antigen 1 and apicoplast proteins using comprehensive immunoinformatics approaches.

Eur J Pharm Sci 2021 Apr 6:105837. Epub 2021 Apr 6.

Zoonotic Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran. Electronic address:

This study was aimed at designing and evaluation of a multimeric vaccine construct against Toxoplasma gondii via utilization of SAG1 along with apicoplast ribosomal proteins (S2, S5 and L11). Top-ranked MHC-I and MHC-II binding as well as shared, immunodominant linear B-cell epitopes were predicted and joined together via appropriate linkers. Also, TLR-4 agonist (RS-09 synthetic protein) and His-tag were added to the N- and C-terminal of the vaccine sequence. Read More

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Herkinorin negatively regulates NLRP3 inflammasome to alleviate neuronal ischemic injury through activating Mu opioid receptor and inhibiting the NF-κB pathway.

J Cell Biochem 2021 Apr 9. Epub 2021 Apr 9.

Department of Neurobiology and Center of Stroke, School of Basic Medical Science, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.

Herkinorin is a novel opioid receptor agonist. Activation of opioid receptors, a member of G protein coupled receptors (GPCRs), may play an important role in Herkinorin neuroprotection. GPCRs may modulate NOD-like receptor protein 3 (NLRP3)-mediated inflammatory responses in the mechanisms of inflammation-associated disease and pathological processes. Read More

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Ferulic acid alleviates abnormal behaviors in isolation-reared mice via 5-HT receptor partial agonist activity.

Psychopharmacology (Berl) 2021 Apr 8. Epub 2021 Apr 8.

Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan.

Rationale: Preclinical and clinical reports suggest that ferulic acid (FA), a plant-derived phenylpropanoid, is effective against mental health problems such as agitation, anxiety, and irritability in humans, without causing adverse side effects. However, the mechanism of action is unknown.

Objective: The aim of the study is to investigate the mechanism underlying the ameliorative effects of FA on mental health problems such as agitation, anxiety, and irritability, using in vivo behavioral analysis, in vitro pharmacological analysis, and in silico binding analysis. Read More

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TRPV1 channels as a newly identified target for vitamin D.

Channels (Austin) 2021 Dec;15(1):360-374

Department of Pharmacology and the Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.

Vitamin D is known to elicit many biological effects in diverse tissue types and is thought to act almost exclusively upon its canonical receptor within the nucleus, leading to gene transcriptional changes and the subsequent cellular response. However, not all the observed effects of vitamin D can be attributed to this sole mechanism, and other cellular targets likely exist but remain to be identified. Our recent discovery that vitamin D is a partial agonist of the Transient Receptor Potential Vanilloid family 1 (TRPV1) channel may provide new insights as to how this important vitamin exerts its biological effects either independently or in addition to the nuclear vitamin D receptor. Read More

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December 2021

Exendin 4-Hapten Conjugate Capable of Binding with Endogenous Antibodies for Peptide Half-life Extension and Exerting Long-Acting Hypoglycemic Activity.

J Med Chem 2021 Apr 7. Epub 2021 Apr 7.

Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 214122 Wuxi, China.

Hapten-specific endogenous antibodies are naturally occurring antibodies present in human blood. Herein, we investigated a new strategy in which small-molecule haptens were utilized as naturally occurring antibody binders for peptide half-life extension. The glucagon-like peptide 1 receptor agonist exendin 4 was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus via sortase A-mediated ligation. Read More

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Lipopolysaccharide Preparation Derived From Induces a Weaker Immuno-Inflammatory Response in BV-2 Microglial Cells Than by Differentially Activating TLR2/4-Mediated NF-κB/STAT3 Signaling Pathways.

Front Cell Infect Microbiol 2021 18;11:606986. Epub 2021 Mar 18.

Department of Periodontology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Alzheimer's disease (AD) is a degenerative disease of the central nervous system with unclear etiology and pathogenesis. In recent years, as the infectious theory and endotoxin hypothesis of AD has gained substantial attention, several studies have proposed that (), one of the main pathogenic bacteria of chronic periodontitis, and the lipopolysaccharide (LPS) of may lead to AD-like pathological changes and cognition impairment. However, research on the relationship between -LPS and neuroinflammation is still lacking. Read More

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Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics.

Front Immunol 2021 18;12:631797. Epub 2021 Mar 18.

Department of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria.

Pro-inflammatory signaling mediated by Toll-like receptor 4 (TLR4)/myeloid differentiation-2 (MD-2) complex plays a crucial role in the instantaneous protection against infectious challenge and largely contributes to recovery from Gram-negative infection. Activation of TLR4 also boosts the adaptive immunity which is implemented in the development of vaccine adjuvants by application of minimally toxic TLR4 activating ligands. The modulation of pro-inflammatory responses via the TLR4 signaling pathway was found beneficial for management of acute and chronic inflammatory disorders including asthma, allergy, arthritis, Alzheimer disease pathology, sepsis, and cancer. Read More

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In silico analysis of molecular interactions between HIV-1 glycoprotein gp120 and TNF receptors.

Infect Genet Evol 2021 Apr 1:104837. Epub 2021 Apr 1.

Department of Pathology, Federal University of Pernambuco, Recife, Pernambuco, Brazil; Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco, Recife, Pernambuco, Brazil.

Proinflammatory microenvironmental is crucial for the Human Immunodeficiency Virus Type 1 (HIV-1) pathogenesis. The viral glycoprotein 120 (gp120) must interact with the CD4+ T cell chemokine receptor (CCR5) and a co-receptor C-X-C chemokine receptor type 4 (CXCR4) to let the virus entry into the host cells. However, the interaction of the viral particle with other cell surface receptors are mandatory for its attachment and subsequently entry. Read More

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In vitro evidence suggesting that the toll-like receptor 7 and 8 agonist resiquimod (R-848) unlikely affects drug levels of co-administered compounds.

Eur J Pharm Sci 2021 Apr 1:105826. Epub 2021 Apr 1.

Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

Resiquimod (R-848) is an immune response modifier activating toll-like receptor 7 and 8. Its potential to cause pharmacokinetic interactions with concurrently administered drugs is unknown. To study the time course of the effect of resiquimod in LS180 cells as a model for intestinal tissue, luciferase-based reporter gene assays and reverse transcription polymerase chain reaction were used to investigate whether resiquimod affects the activities of nuclear factor kappa B (NF-ĸB), pregnane x receptor (PXR) or the transcription of selected central genes for drug disposition (cytochrome P-450 isozyme 3A4 (CYP3A4), CYP1A1, UDP-glucuronosyltransferase 1A1 (UGT1A1), ATP-binding cassette transporters ABCC2, ABCB1). Read More

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Identification of novel pregnane X receptor (PXR) agonists by In silico and biological activity analyses and reversal of cigarette smoke-induced PXR downregulation.

Biochem Biophys Res Commun 2021 Mar 30;555:1-6. Epub 2021 Mar 30.

Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA; VA Pittsburgh Healthcare System, Pittsburgh, PA, 15240, USA. Electronic address:

Cigarette smoke (CS) contains many toxins that collectively harm nearly every organ in the body, and smoking is a key risk factor for many chronic diseases. Aside from its toxic actions, CS may alter expression of the drug- and steroid-binding pregnane X receptor (PXR), which when activated upregulates expression of cytochrome P450 (CYP) enzymes, glutathione transferases (GSTs), and multidrug resistance protein 1 (MDR1), an adaptive metabolic array that mediates clearance of CS component toxins. We sought to identify new PXR agonists that may be useful for restoring PXR activity in conditions wherein it is suppressed, and their mechanisms of PXR binding and activation. Read More

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Co-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery.

Int J Mol Sci 2021 Mar 19;22(6). Epub 2021 Mar 19.

School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK.

Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepancies in understanding the complex role of PPARβ/δ in disease, having both anti- and pro-effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. Read More

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MRAP2 Interaction with Melanocortin-4 Receptor in SnakeHead ().

Biomolecules 2021 Mar 23;11(3). Epub 2021 Mar 23.

Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.

The melanocortin-4 receptor (MC4R) plays an important role in the regulation of food intake and energy expenditure. Melanocortin-2 receptor accessory protein 2 (MRAP2) modulates trafficking, ligand binding, and signaling of MC4R. The Northern snakehead () is an economically important freshwater fish native to East Asia. Read More

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The Open Question of How GPCRs Interact with GPCR Kinases (GRKs).

Biomolecules 2021 Mar 17;11(3). Epub 2021 Mar 17.

Departments of Biological Sciences and Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.

G protein-coupled receptors (GPCRs), which regulate a vast number of eukaryotic processes, are desensitized by various mechanisms but, most importantly, by the GPCR kinases (GRKs). Ever since GRKs were first identified, investigators have sought to determine which structural features of GRKs are used to select for the agonist-bound states of GPCRs and how this binding event in turn enhances GRK catalytic activity. Despite a wealth of molecular information from high-resolution crystal structures of GRKs, the mechanisms driving activation have remained elusive, in part because the GRK N-terminus and active site tether region, previously proposed to serve as a receptor docking site and to be key to kinase domain closure, are often disordered or adopt inconsistent conformations. Read More

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CXCL10 Is an Agonist of the CC Family Chemokine Scavenger Receptor ACKR2/D6.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health (LIH), L-4354 Esch-sur-Alzette, Luxembourg.

Atypical chemokine receptors (ACKRs) are important regulators of chemokine functions. Among them, the atypical chemokine receptor ACKR2 (also known as D6) has long been considered as a scavenger of inflammatory chemokines exclusively from the CC family. In this study, by using highly sensitive β-arrestin recruitment assays based on NanoBiT and NanoBRET technologies, we identified the inflammatory CXC chemokine CXCL10 as a new strong agonist ligand for ACKR2. Read More

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Compound- and fiber type-selective requirement of AMPKγ3 for insulin-independent glucose uptake in skeletal muscle.

Mol Metab 2021 Mar 30:101228. Epub 2021 Mar 30.

Nestlé Research, Société des Produits Nestlé S.A., EPFL Innovation Park, Lausanne, 1015, Switzerland; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark. Electronic address:

Objective: The metabolic master-switch AMP-activated protein kinase (AMPK) mediates insulin-independent glucose uptake in muscle and regulates the metabolic activity of brown and beige adipose tissue (BAT). The regulatory AMPKγ3 isoform is uniquely expressed in skeletal muscle and also potentially in BAT. Here, we investigated the role that AMPKγ3 plays in mediating skeletal muscle glucose uptake and whole-body glucose clearance in response to small-molecule activators that act on AMPK via distinct mechanisms. Read More

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COR758, a negative allosteric modulator of GABA receptors.

Neuropharmacology 2021 Mar 30;189:108537. Epub 2021 Mar 30.

Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, Italy; Guy Everett Laboratory, University of Cagliari, 09042, Monserrato, Italy; Center of Excellence "Neurobiology of Addiction", University of Cagliari, 09042, Monserrato, Italy. Electronic address:

Allosteric modulators of G protein coupled receptors (GPCRs), including GABARs (GABARs), are promising therapeutic candidates. While several positive allosteric modulators (PAM) of GABARs have been characterized, only recently the first negative allosteric modulator (NAM) has been described. In the present study, we report the characterization of COR758, which acts as GABAR NAM in rat cortical membranes and CHO cells stably expressing GABARs (CHO-GABA). Read More

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Toll-like receptor activation of equine mesenchymal stromal cells to enhance antibacterial activity and immunomodulatory cytokine secretion.

Vet Surg 2021 Apr 2. Epub 2021 Apr 2.

Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Colorado, USA.

Objective: To evaluate effects of Toll-like and nucleotide-binding oligomerization domain (NOD)-like receptor (TLR, NLR) ligand stimulation of equine mesenchymal stromal cells (MSCs) on antibacterial and immunomodulatory properties in vitro.

Study Design: Controlled laboratory study.

Sample Population: Equine bone-marrow-derived MSCs (three horses). Read More

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Effect of TO901317 on GF to promote the differentiation of human bone marrow mesenchymal stem cells into dopamine neurons on Parkinson's disease.

Ther Adv Chronic Dis 2021 19;12:2040622321998139. Epub 2021 Mar 19.

College of Pharmacy, Chongqing Medical University, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing, 400016, China.

Background: Human bone marrow mesenchymal stem cells (hBMSCs) could differentiate into dopamine-producing cells and ameliorate behavioral deficits in Parkinson's disease (PD) models. Liver X receptors (LXRs) are involved in the maintenance of the normal function of central nervous system myelin. Therefore, the previous work of our team has found the induction of cocktail-induced to dopaminergic (DA) phenotypes from adult rat BMSCs by using sonic hedgehog (SHH), fibroblast growth factor 8 (FGF8), basic fibroblast growth factor (bFGF), and TO901317 (an agonist of LXRs) with 87. Read More

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Stability of the Retinoid X Receptor-α Homodimer in the Presence and Absence of Rexinoid and Coactivator Peptide.

Biochemistry 2021 Apr 1. Epub 2021 Apr 1.

Department of Biochemistry & Molecular Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.

Differential scanning calorimetry and differential scanning fluorimetry were used to measure the thermal stability of human retinoid X receptor-α ligand binding domain (RXRα LBD) homodimer in the absence or presence of rexinoid and coactivator peptide, GRIP-1. The -RXRα LBD homodimer displayed a single thermal unfolding transition with a of 58.7 °C and an unfolding enthalpy (Δ) of 673 kJ/mol (12. Read More

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Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder.

ACS Chem Neurosci 2021 Apr 1. Epub 2021 Apr 1.

Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, 70125 Bari, Italy.

Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders characterized by core symptoms such as impaired social interaction and communication, repetitive and stereotyped behaviors, and restricted interests. To date, there are no effective treatments for these core symptoms. Several studies have shown that the brain serotonin (5-HT) neurotransmission system is altered in both ASD patients and animal models of the disease. Read More

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Generation and characterization of a high-affinity chimeric anti-OX40 antibody with potent anti-tumor activity.

FEBS Lett 2021 Mar 31. Epub 2021 Mar 31.

Shanghai ChemPartner Co., Ltd, Shanghai, China.

OX40 is a costimulatory molecule that belongs to the tumor necrosis factor receptor (TNFR) superfamily. OX40 agonist-based combinations are emerging as promising candidates for novel cancer immunotherapy. Clinical trials have shown that OX40 agonist antibodies could lead to better results in cancer patients. Read More

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Liver X receptor agonist GW3965 protects against sepsis by promoting myeloid derived suppressor cells apoptosis in mice.

Life Sci 2021 Mar 27;276:119434. Epub 2021 Mar 27.

Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Hunan, China; Department of Pathophysiology, Xiangya School of Medicine, Central South University, Hunan, China. Electronic address:

Aims: Immunosuppressive myeloid-derived suppressor cells (MDSCs) continuously expand and lead to poor outcome during sepsis. The activation of liver X receptor (LXR) can mitigate sepsis-induced liver and myocardial damage. This study aims to determine whether LXR plays a protective role in sepsis by regulating MDSCs. Read More

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Design, synthesis, and biological evaluation of a novel dual peroxisome proliferator-activated receptor alpha/delta agonist for the treatment of diabetic kidney disease through anti-inflammatory mechanisms.

Eur J Med Chem 2021 Mar 20;218:113388. Epub 2021 Mar 20.

Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, China. Electronic address:

Diabetic kidney disease (DKD) is a major feature of the final stage of nearly all cause types of diabetes mellitus (DM). To date, few safe and effective drugs are available to treat. Peroxisome proliferator-activated receptors (PPARs), comprised of three members: PPAR-α, PPAR-δ and PPAR-γ, play a protective role in the DKD through glycemic control and lipid metabolism, whereas systemic activation of PPAR-γ causes serious side-effects in clinical trials. Read More

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PPARγ activation improves the microenvironment of perivascular adipose tissue and attenuates aortic stiffening in obesity.

J Biomed Sci 2021 Mar 29;28(1):22. Epub 2021 Mar 29.

Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.

Background: Obesity-related cardiovascular risk, end points, and mortality are strongly related to arterial stiffening. Current therapeutic approaches for arterial stiffening are not focused on direct targeting within the vessel. Perivascular adipose tissue (PVAT) surrounding the artery has been shown to modulate vascular function and inflammation. Read More

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