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Receptors And Lead Compound

Chelsea A O'Driscoll, Leah A Owens, Erica J Hoffmann, Madeline E Gallo, Amin Afrazi, Mei Han, John H Fechner, James J Schauer, Christopher A Bradfield, Joshua D Mezrich
BACKGROUND: Autoimmune diseases have increased in incidence and prevalence worldwide. While genetic predispositions play a role, environmental factors are a major contributor. Atmospheric particulate matter (PM) is a complex mixture composed of metals, nitrates, sulfates and diverse adsorbed organic compounds like polycyclic aromatic hydrocarbons (PAHs) and dioxins. Exposure to atmospheric PM aggravates autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, among others...
October 1, 2018: Environmental Research
Himgauri Naik, Ted Gauthier, Sitanshu Singh, Seetharama Jois
The human epidermal growth factor receptor (EGFR) family is known to be involved in cell signaling pathways. The extracellular domain of EGFR consists of four domains, of which domain II and domain IV are known to be involved in the dimerization process. Overexpression of these receptors is known to play a significant role in heterodimerization of these receptors leading to the development of cancer. We have designed peptidomimetic molecules to inhibit the EGFR heterodimerization interaction that have shown antiproliferative activity and specificity for HER2-positive cancer cell lines...
October 3, 2018: Bioorganic & Medicinal Chemistry Letters
Christina Susan Abraham, S Muthu, Johanan Christian Prasana, Sanja J Armaković, Stevan Armaković, Fathima Rizwana B, Ben Geoffrey A S
Spectroscopic profiling in terms of FT-IR, FT-Raman, UV-vis and NMR in addition to reactivity study by density functional theory (DFT) and molecular dynamics (MD) simulations of 3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine (C16 H19 ClN2 ) have been discussed. In order to assign principal vibrational numbers, the Potential energy distribution (PED) analysis has been executed. Frontier molecular orbitals (FMOs) analysis in addition to the stabilization energy and natural hybrid orbital analysis has been done...
September 3, 2018: Computational Biology and Chemistry
Bernhard Wünsch, Simone Thum, Dirk Schepmann, Dmitrii V Kalinin, Simon M Ametamey
The 4-benzylpiperidine moiety represents a central structural element of potent N-methyl-D-aspartate (NMDA) receptor antagonists containing the GluN2B subunit. In order to obtain novel GluN2B ligands suitable for positron emission tomography the benzylpiperidine moiety was replaced by fluorinated ω-phenylalkylamino groups. For this purpose three primary propyl- and butylamines 7a-c and one butyraldehyde 7d bearing a fluorine atom and an ω-phenyl moiety were prepared in 3-7 step syntheses. 7a d were attached to various scaffolds of potent GluN2B antagonists (scaffold hopping) instead of the original 4-benzylpiperidine moiety...
October 12, 2018: ChemMedChem
Anne Schink, Jan Neumann, Anna Lena Leifke, Kira Ziegler, Janine Fröhlich-Nowoisky, Christoph Cremer, Eckhard Thines, Bettina Weber, Ulrich Pöschl, Detlef Schuppan, Kurt Lucas
Herbal extracts represent an ample source of natural compounds, with potential to be used in improving human health. There is a growing interest in using natural extracts as possible new treatment strategies for inflammatory diseases. We therefore aimed at identifying herbal extracts that affect inflammatory signaling pathways through toll-like receptors (TLRs), TLR2 and TLR4. Ninety-nine ethanolic extracts were screened in THP-1 monocytes and HeLa-TLR4 transfected reporter cells for their effects on stimulated TLR2 and TLR4 signaling pathways...
2018: PloS One
S Prekovic, T van den Broeck, S Linder, M E van Royen, A B Houtsmuller, F Handle, S Joniau, W Zwart, F Claessens
Prostate cancer (PCa) is among the most common adult malignancies, and the second leading cause of cancer-related death in men. As PCa is hormone dependent, blockade of the androgen receptor (AR) signaling is an effective therapeutic strategy for men with advanced metastatic disease. The discovery of enzalutamide, a compound that effectively blocks the AR axis and its clinical application has led to a significant improvement in survival time. However, the effect of enzalutamide is not permanent, and resistance to treatment ultimately leads to development of lethal disease, for which there currently is no cure...
November 1, 2018: Endocrine-related Cancer
Kaveri Arora, Jeffrey M Sequeira, Juan M Alarcon, Brandi Wasek, Erland Arning, Teodoro Bottiglieri, Edward V Quadros
In humans, vitamin B12 deficiency causes peripheral and CNS manifestations. Loss of myelin in the peripheral nerves and the spinal cord (SC) contributes to peripheral neuropathy and motor deficits. The metabolic basis for the demyelination and brain disorder is unknown. The transcobalamin receptor-knockout mouse ( Cd320-/- ) develops cobalamin (Cbl) deficiency in the nervous system, with mild anemia. A decreased S-adenosylmethionine: S-adenosylhomocysteine ratio and increased methionine were seen in the brain with no significant changes in neurotransmitter metabolites...
October 10, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Nivedita Singh, Ashwinee Kumar Shreshtha, M S Thakur, Sanjukta Patra
Medicinal plants have been the basis for discovery of various important marketed drugs. Xanthine is one such lead molecule. Xanthines in various forms (caffeine, theophylline, theobromine, etc) are abode in tea, coffee, cocoa, chocolate etc. giving them popular recognition. These compounds are best known for their diverse pharmaceutical applications as cyclic nucleotide phosphodiesterase inhibition, antagonization of adenosine receptor, anti-inflammatory, anti-microbial, anti-oxidant and anti-tumor activities...
October 2018: Heliyon
Issan Zhang, Maja Beus, Ursula Stochaj, Phuong Uyen Le, Branka Zorc, Zrinka Rajić, Kevin Petrecca, Dusica Maysinger
Glioblastoma multiforme is one of the most aggressive brain tumors and current therapies with temozolomide or suberoylanilide hydroxamic acid (SAHA, vorinostat) show considerable limitations. SAHA is a histone deacetylase (HDAC) inhibitor that can cause undesirable side effects due to the lack of selectivity. We show here properties of a novel hybrid molecule, sahaquine, which selectively inhibits cytoplasmic HDAC6 at nanomolar concentrations without markedly suppressing class I HDACs. Inhibition of HDAC6 leads to significant α-tubulin acetylation, thereby impairing cytoskeletal organization in glioblastoma cells...
2018: Cell Death Discovery
Yoshikazu Sasaki, Masahide Odan, Shiho Yamamoto, Shiro Kida, Azumi Ueyama, Masaya Shimizu, Takayo Haruna, Ayahisa Watanabe, Takayuki Okuno
The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, RORγ t is an attractive drug target for such Th17-mediated autoimmune diseases. A structure-activity relationship (SAR) study of lead compound 1 yielded a novel series of RORγ t inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable RORγ t inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration...
September 27, 2018: Bioorganic & Medicinal Chemistry Letters
Asma Elmabruk, Banibrata Das, Deepthi Yedlapudi, Liping Xu, Tamara Antonio, Maarten E A Reith, Aloke K Dutta
We have developed a series of carbazole-derived compounds based on our hybrid D2/D3 agonist template to design multifunctional compounds for the symptomatic and disease-modifying treatment of Parkinson's disease (PD). The lead molecules (-)-11b, (-)-15a and (-)-15c exhibited high affinity for both D2 and D3 receptors where as in GTPγS functional assay, the compounds showed potent agonist activity at both D2 and D3 receptors (EC50 (GTPγS); D2 = 48.7 nM, D3 = 0.96 nM for 11b, D2 = 0.87 nM, D3 = 0.23 nM for 15a and D2 = 2...
October 9, 2018: ACS Chemical Neuroscience
Zheng Li, Zongtao Zhou, Fengjian Deng, Yuyi Li, Danjun Zhang, Luyong Zhang
The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptors (PPARs) have attracted interest as potent targets for the treatment of metabolic syndrome such as type 2 diabetes. Based on the hypothesis that the dual agonists of PPARs and FFA1 would act as insulin sensitizers and secretagogues by simultaneous activation of PPARs and FFA1, we developed the design strategy to obtain dual PPARs/FFA1 agonist by hybrid FFA1 agonist 1 with PPARδ agonist 2 in consideration of their structural similarity...
October 1, 2018: European Journal of Medicinal Chemistry
David Kalbermatter, Neeta Shrestha, Nadine Ader-Ebert, Michael Herren, Pascal Moll, Richard K Plemper, Karl-Heinz Altmann, Johannes P Langedijk, Flavio Gall, Urs Lindenmann, Rainer Riedl, Dimitrios Fotiadis, Philippe Plattet
Morbilliviruses (e.g. measles virus [MeV] or canine distemper virus [CDV]) employ the attachment (H) and fusion (F) envelope glycoproteins for cell entry. H protein engagement to a cognate receptor eventually leads to F-triggering. Upon activation, F proteins transit from a prefusion to a postfusion conformation; a refolding process that is associated with membrane merging. Small-molecule morbilliviral fusion inhibitors such as the compound 3 G (a chemical analog in the AS-48 class) were previously generated and mechanistic studies revealed a stabilizing effect on morbilliviral prefusion F trimers...
October 5, 2018: Virus Research
Artur Jan Kiepura, Andrzej Kochański
Charcot‑Marie‑Tooth type 1A (CMT1A) is a dysmyelinating disease of the peripheral nervous system that results in a slow progressive weakening and wasting of the distal muscles of the upper and lower limbs. Despite extensive research and clinical trials there is still no treatment for CMT1A that results in complete neurological improvement. Recent studies investigating various pharmacological modulators of adenylyl cyclase activity, including ascorbic acid and ligands of G protein‑coupled receptors (GPCRs), provide hope for future treatments of this type of hereditary motor and sensory neuropathy...
2018: Acta Neurobiologiae Experimentalis
Selvaraman Nagamani, Karthikeyan Muthusamy
The level of the vitamin D in the bloodstream is regulated by cytochrome P450 enzyme 24-hydroxylase A1 (CYP24A1). Over expression of CYP24A1 enzyme is correlated with vitamin D deficiency and resistance to vitamin D therapy. Chronic kidney disease (CKD) patients are commonly reported with the above said expression variations. This deregulation could be solved by ligands that act as a vitamin D receptor (VDR) agonists and CYP24A1 antagonists. Posner et al., (2010) first time reported two new vitamin D analogues namely CTA-091 and CTA-018 to inhibit CYP24A1...
2018: PloS One
Martyna Plens-Galaska, Malgorzata Szelag, Aida Collado, Patrice Marques, Susana Vallejo, Mariella Ramos-González, Joanna Wesoly, María Jesus Sanz, Concepción Peiró, Hans A R Bluyssen
Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119...
2018: Frontiers in Immunology
Rafał Kurczab, Wesam Ali, Dorota Łażewska, Magdalena Kotańska, Magdalena Jastrzębska-Więsek, Grzegorz Satała, Małgorzata Więcek, Annamaria Lubelska, Gniewomir Latacz, Anna Partyka, Małgorzata Starek, Monika Dąbrowska, Anna Wesołowska, Claus Jacob, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik
This study focuses on the design, synthesis, biological evaluation, and computer-aided structure-activity relationship (SAR) analysis for a novel group of aromatic triazine-methylpiperazines, with an hydantoin spacer between 1,3,5-traizine and the aromatic fragment. New compounds were synthesized and their affinities for serotonin 5-HT₆, 5-HT1A , 5-HT2A , 5-HT₇, and dopamine D₂ receptors were evaluated. The induced-fit docking (IFD) procedure was performed to explore the 5-HT₆ receptor conformation space employing two lead structures...
October 3, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Carolina Noble, Annelies Cannaert, Kristian Linnet, Christophe P Stove
Synthetic cannabinoids (SCs) are the most chemically diverse group of new psychoactive substances. This group has been associated with several intoxications, many with fatal outcomes. Although advancements have been achieved in pharmacology, metabolism and detection of these compounds in the last years, these aspects are still unresolved for many SCs. The aim of this study was to investigate the in vitro potency of fourteen indole- and indazole-based SCs by applying a stable CB1 or CB2 receptor activation assay and correlate the activity with their structure...
October 2, 2018: Drug Testing and Analysis
Alessio Borio, Aurora Holgado, Rudi Beyaert, Holger Heine, Alla Zamyatina
Toll-like receptor 4 (TLR4) - a transmembrane pattern recognition receptor responsible for propagating the immediate immune response to Gram-negative bacterial infection - plays the central role in the pathogenesis of sepsis as well as chronic inflammation-related disorders and represents a target of choice for establishing new anti-inflammatory treatment strategies. Despite significant advances made in the last decade in the understanding of molecular mechanisms underlying the progression of sepsis and in the development of clinically relevant therapies, sepsis remains the leading cause of mortality in intensive care units with increasing incidence worldwide...
October 1, 2018: ChemMedChem
Kalina Atkovska, Johannes Klingler, Johannes Oberwinkler, Sandro Keller, Jochen S Hub
Steroids have numerous physiological functions associated with cellular signaling or modulation of the lipid membrane structure and dynamics, and as such, they have found broad pharmacological applications. Steroid-membrane interactions are relevant to multiple steps of steroid biosynthesis and action, as steroids are known to interact with neurotransmitter or membrane steroid receptors, and steroids must cross lipid membranes to exert their physiological functions. Therefore, rationalizing steroid function requires understanding of steroid-membrane interactions...
September 26, 2018: ACS Central Science
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