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Receptors And Lead Compound

Shu-Yu Lin, Yu-Hsien Kuo, Ya-Wen Tien, Yi-Yu Ke, Wan-Ting Chang, Hsiao-Fu Chang, Li-Chin Ou, Ping-Yee Law, Jing-Hua Xi, Pao-Luh Tao, Horace H Loh, Yu-Sheng Chao, Chuan Shih, Chiung-Tong Chen, Shiu-Hwa Yeh, Shau-Hua Ueng
Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However, prolonged activation of MOR also results in tolerance, dependence, addiction, constipation, nausea, sedation, and respiratory depression. To address this problem, we sought alternative ways to activate MOR - either by use of novel ligands, or via a novel activation mechanism. To this end, a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR® calcium high-throughput screening (HTS) assay, and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone...
February 2, 2019: European Journal of Medicinal Chemistry
Maxwell M Sakyiamah, Takuya Kobayakawa, Masayuki Fujino, Makoto Konno, Tetsuo Narumi, Tomohiro Tanaka, Wataru Nomura, Naoki Yamamoto, Tsutomu Murakami, Hirokazu Tamamura
The chemokine receptor CXCR4/stromal cell-derived factor-1 (SDF-1: CXCL12) signaling axis represents a crucial drug target due to its relevance to several diseases such as HIV-1 infection, cancer, leukemia, and rheumatoid arthritis. With the aim of enhancing the binding affinity and anti-HIV activity of a potent CXCR4 ligand as a lead, 23 low molecular weight compounds containing dipicolylamine (Dpa) and cyclam cationic moieties with varying spacers and spatial positioning were designed, synthesized and biologically evaluated...
February 6, 2019: Bioorganic & Medicinal Chemistry
Xiao-Yi Jia, Yan Chang, Xiao-Jing Sun, Fang Wei, Yu-Jing Wu, Xing Dai, Shu Xu, Hua-Xun Wu, Chun Wang, Xue-Zhi Yang, Wei Wei
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. Dendritic cells (DCs) are one of the most powerful antigen-presenting cells, and they play an important role in RA pathogenesis. Prostaglandin E2 (PGE2) is a potent lipid mediator that can regulate the maturation and activation of DCs, but the molecular mechanisms have not been elucidated. In this study, both in vitro and in an RA rat model, we investigated the mechanisms involved by focusing on PGE2-mediated signaling and using a novel anti-inflammatory compound, paeoniflorin-6'-O-benzene sulfonate (CP-25)...
February 15, 2019: Inflammopharmacology
Shinri Horoiwa, Taiyo Yokoi, Satoru Masumoto, Saki Minami, Chiharu Ishizuka, Hidetoshi Kishikawa, Shunsuke Ozaki, Shigeki Kitsuda, Yoshiaki Nakagawa, Hisashi Miyagawa
The ecdysone receptor (EcR) is an insect nuclear receptor that is activated by the molting hormone, 20-hydroxyecdysone. Because synthetic EcR ligands disrupt the normal growth of insects, they are attractive candidates for new insecticides. In this study, the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method was used to predict the binding activity of EcR ligands. Validity analyses using 40 known EcR ligands showed that the binding activity was satisfactorily predicted when the ligand conformational free energy term was introduced...
February 5, 2019: Bioorganic & Medicinal Chemistry
Xinshan Deng, Xiaoyu Tan, Tiantian An, Qingqing Ma, Zhe Jin, Ce Wang, Qingguo Meng, Chun Hu
Based on the analysis of epidermal growth factor receptor (EGFR) complexes with gefitinib with molecular docking, the scaffold-hopping strategy, combination of the active substructures, and structural optimization of EGFR inhibitors, a novel series of benzo[4,5]imidazo[2,1- b ]thiazole derivatives was designed, synthesized, and evaluated for antitumor activity in human cancer cell lines and cellular toxicity against human normal cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay and EGFR inhibitory activities in vitro...
February 14, 2019: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Panteleimon Pantelidis, Michail Sideris, Margus Viigimaa, Konstantinos Avranas, Pavlos Deligkaris, Ioanna Zografou, Dragan Lovic
BACKGROUND: Aldosterone, through its actions on Mineralcorticosteroid Receptors (MR), controls fluid and electrolyte balance, but also exerts various direct deleterious actions on the vasculature. A number of aldosterone antagonists have been manufactured to reverse these effects. OBJECTIVE: A comprehensive review of the underlying mechanisms of the actions of aldosterone and its antagonists in cardiovascular disease. METHOD: The relevant studies indexed in PubMed, Scopus and Google Scholar databases, published from 2003 to May 2018 were identified and reported...
February 14, 2019: Current Pharmaceutical Design
Pierre Guillet, Florian Mahler, Kelly Garnier, Gildas Nyame Mendendy Boussambe, Sébastien Igonet, Carolyn Vargas, Christine Ebel, Marine Soulié, Sandro Keller, Anass Jawhari, Grégory Durand
We report herein the design and synthesis of a novel series of alkyl glycosides detergents consisting of a nonionic polar headgroup that comprises two glucose moieties in a branched arrangement (DG), onto which octane-, decane- and dodecanethiols were grafted leading to ODG, DDG, and DDDG detergents. Micellization in aqueous solution was studied by isothermal titration calorimetry (ITC), 1H NMR spectroscopy, and surface tensiometry (SFT). Critical micellar concentration values were found to decrease by a factor of ~10 for each pair of methylene groups added to the alkyl chain, ranging from ~0...
February 15, 2019: Langmuir: the ACS Journal of Surfaces and Colloids
Anna N Berlina, Anatoly V Zherdev, Boris B Dzantiev
This review (with 230 refs.) covers recent progress in rapid optical assays for heavy metals (primarily lead and mercury as the most relevant) based on the use of nanoparticles and receptor molecules. An introduction surveys the importance, regulatory demands (such as maximum permissible concentrations) and potential and limitations of various existing methods. This is followed by a general discussion on the use of nanoparticles in optical assays of heavy metals (including properties, basic mechanisms of signal generation)...
February 14, 2019: Mikrochimica Acta
Meizi Wang, Xinlu Li, Mengting Chen, Xiaoqing Wu, Yiduo Mi, Zhenpeng Kai, Xinling Yang
Allatostatins (AST) are neuropeptides originally described as inhibitors of juvenile hormone (JH) synthesis in insects. Consequently, they have been considered as potential lead compounds for the discovery of new insect growth regulators (IGRs). In the present work, receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) was studied with 48 AST analogs, and a general approach for novel potent bioactive AST analogs is proposed. Hence, six novel AST analogs were designed and synthesized...
February 2, 2019: Bioorganic & Medicinal Chemistry Letters
Shouta Miyatake, Yoshitaka Mizobe, Maria K Tsoumpra, Kenji Rowel Q Lim, Yuko Hara, Fazel Shabanpoor, Toshifumi Yokota, Shin'ichi Takeda, Yoshitsugu Aoki
Exon skipping using phosphorodiamidate morpholino oligomers (PMOs) is a promising treatment strategy for Duchenne muscular dystrophy (DMD). The most significant limitation of these clinically used compounds is their lack of delivery systems that target muscles; thus, cell-penetrating peptides are being developed to enhance uptake into muscles. Recently, we reported that uptake of peptide-conjugated PMOs into myofibers was mediated by scavenger receptor class A (SR-A), which binds negatively charged ligands...
January 25, 2019: Molecular Therapy. Nucleic Acids
Jianxiong Jiang, Ying Yu, Erika Kinjo, Yifeng Du, Hoang Nguyen, Ray Dingledine
Glutamate receptor-mediated excitotoxicity is a common pathogenic process in many neurological conditions including epilepsy. Prolonged seizures induce elevations in extracellular glutamate that contribute to excitotoxic damage, which in turn can trigger chronic neuroinflammatory reactions, leading to secondary damage to the brain. Blocking key inflammatory pathways could prevent such secondary brain injury following the initial excitotoxic insults. Prostaglandin E2 (PGE2 ) has emerged as an important mediator of neuroinflammation-associated injury, in large part via activating its EP2 receptor subtype...
February 11, 2019: Neuropharmacology
Chiachen Chen, Mary Beth Breslin, Jessie J Guidry, Michael S Lan
Insulinoma associated-1 (INSM1) is a key protein functioning as a transcriptional repressor in neuroendocrine differentiation and is activated by N-Myc in human neuroblastoma (NB). INSM1 modulates the phosphoinositide 3-kinase (PI3K)-AKT Ser/Thr kinase (AKT)-glycogen synthase kinase 3β (GSK3β) signaling pathway through a positive-feedback loop, resulting in N-Myc stabilization. Accordingly, INSM1 has emerged as a critical player closely associated with N-Myc in facilitating NB cell growth. Here, an INSM1 promoter-driven luciferase-based screen revealed that the compound 5'-iodotubercidin suppresses adenosine kinase (ADK), an energy pathway enzyme, and also INSM1 expression and NB tumor growth...
February 12, 2019: Journal of Biological Chemistry
Kazutaka Ikegashira, Taku Ikenogami, Takayuki Yamasaki, Takahiro Oka, Yasunori Hase, Naoki Miyagawa, Koji Inagaki, Iichiro Kawahara, Yoshihisa Koga, Hiromasa Hashimoto
Optimization of novel azetidine compounds, which we had found as colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors, provided JTE-952 as a clinical candidate with high cellular activity (IC50  = 20 nM) and good pharmacokinetics profile. JTE-952 was also effective against a mouse collagen-induced model of arthritis (mouse CIA-model). Additionally, the X-ray co-crystal structure of JTE-952 with CSF-1R protein was shown to be a Type II inhibitor, and the kinase panel assay indicated that JTE-952 had high kinase selectivity...
February 7, 2019: Bioorganic & Medicinal Chemistry Letters
Quang T Nguyen, Mohamed Jalloul Nsaibia, Martin G Sirois, Angelino Calderone, Jean-Claude Tardif, Yan Fen Shi, Matthieu Ruiz, Caroline Daneault, Lyne Gagnon, Brigitte Grouix, Pierre Laurin, Jocelyn Dupuis
Aims: Heart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model. Methods and Results: HFrEF was induced after myocardial infarction (MI) in rats...
February 7, 2019: Cardiovascular Research
Nitin Chitranshi, Yogita Dheer, Sanjay Kumar, Stuart L Graham, Vivek Gupta
Retinoid X receptors (RXRs) belong to the nuclear receptor superfamily, and upon ligand activation, these receptors control gene transcription via either homodimerization with themselves or heterodimerization with the partner-nuclear receptor. The protective effects of RXRs and RXR agonists have been reported in several neurodegenerative diseases, including in the retina. This study was aimed to prioritize compounds from natural and synthetic origin retinoids as potential RXR agonists by molecular docking and molecular dynamic simulation strategies...
February 11, 2019: Journal of Cellular Biochemistry
Iman Daryaei, Karin Sandoval, Ken Witt, Maria Kontoyianni, A Michael Crider
A series of compounds containing a 1,2,4-triazole moiety were synthesized, targeting the somatostatin receptor subtype-4 (sst4 ). Compounds were developed in which the Phe6 /Phe7 /Phe11 , Trp8 , and Lys9 mimetic groups were interchanged at positions 3, 4, and 5 of the 1,2,4-triazole ring. The 1,2,4-triazoles containing an 2-(imidazol-4-yl)ethyl substituent at position-3 demonstrated moderate binding affinity at sst4 . 1,2,4-Triazoles containing an (indol-3-yl)methyl substituent at position-5 lacked affinity at sst4 ...
December 1, 2018: MedChemComm
Penghua Fang, Biao He, Mei Yu, Mingyi Shi, Yan Zhu, Zhenwen Zhang, Ping Bo
Overweight and obesity may cause several metabolic complications, including type 2 diabetes mellitus and hyperlipidemia. Despite years of progress in medicine, there are no highly effective pharmacological treatments for obesity. The natural compound celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, exerts various bioactivities including anti-diabetic and anti-obese effects. Although celastrol could decrease food intake and obesity, the detailed mechanism for celastrol is still unclear as yet...
February 8, 2019: Biochimica et biophysica acta. Molecular basis of disease
Tanja Frank, Marcel Tuppi, Manuela Hugle, Volker Dötsch, Sjoerd J L van Wijk, Simone Fulda
Resistance to apoptosis is a hallmark of cancer and deregulation of apoptosis often leads to chemoresistance. Therefore, new approaches to target apoptosis-resistant cancer cells are crucial for the development of directed cancer therapies. In the present study, we investigated the effect of cell cycle regulators on interferon (IFN)-induced necroptosis as an alternative cell death mechanism to overcome apoptosis resistance. Here, we report a novel combination treatment of IFNs with cell cycle arrest-inducing compounds that induce necroptosis in apoptosis-resistant cancer cells and elucidate the underlying molecular mechanisms...
February 11, 2019: Cell Death and Differentiation
Dabo Pan, Chen Zeng, Weiyang Zhang, Ting Li, Zifei Qin, Xiaojun Yao, Yi Dai, Zhihong Yao, Yang Yu, Xinsheng Yao
In this study, an efficient strategy developed by integrating UPLC-Q/TOF-MS, network pharmacology, and molecular simulation, was proposed and applied for rapidly screening bioactive candidates from ginger. A UPLC-Q/TOF MS-guided isolation targeting non-volatile pungent compounds resulted in the isolation and identification of 19 compounds in the rhizome of Zingiber officinale, including six new compounds (1-6). Based on target prediction and Gene Ontology (GO), the primary biological function of compounds was predicted to be associated with cancer and the key target was VEGFR2 (vascular endothelial growth factor receptor 2)...
February 11, 2019: Food & Function
Mehdi Farokhnia, Monica L Faulkner, Daria Piacentino, Mary R Lee, Lorenzo Leggio
Alcohol use disorder (AUD) is a leading cause of morbidity and mortality worldwide. However, treatment options, including pharmacotherapies, are limited in number and efficacy. Accumulating evidence suggests that elements of the gut-brain axis, such as neuroendocrine pathways and gut microbiome, are involved in the pathophysiology of AUD and, therefore, may be investigated as potential therapeutic targets. One pathway that has begun to be examined in this regard is the ghrelin system. Here, we review preclinical and clinical data on the relationship between ghrelin and alcohol-related outcomes, with a special focus on the role of the ghrelin system as a treatment target for AUD...
February 7, 2019: Physiology & Behavior
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