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Molecular Pharmacology

Daniel E O'Brien, Douglas M Shaw, Hyekyung P Cho, Alan J Cross, Steven S Wesolowski, Andrew S Felts, Jonas Bergare, Charles S Elmore, Craig W Lindsley, Colleen M Niswender, P Jeffrey Conn
Allosteric modulation of metabotropic glutamate receptor 2 (mGlu2) has demonstrated efficacy in preclinical rodent models of several brain disorders, leading to industry and academic drug discovery efforts. Although the pharmacology and binding sites of some mGlu2 allosteric modulators have been characterized previously, questions remain about the nature of the allosteric mechanism of cooperativity with glutamate and whether structurally diverse allosteric modulators bind in an identical manner to specific allosteric sites...
March 15, 2018: Molecular Pharmacology
Rebecca C Allsopp, Sudad Dayl, Anfal Bin Dayel, Ralf Schmid, Richard J Evans
P2X7 receptor (P2X7Rs) activation requires ~ 100 fold higher concentrations of ATP than other P2XR subtypes. Such high levels are found during cellular stress and P2X7Rs consequently contribute to a range of pathophysiological conditions. We have used chimeric and mutant P2X7Rs, coupled with molecular modelling, to produce a validated model of the binding mode of the subtype selective antagonist A438079 at an inter-subunit allosteric site. Within the allosteric site large effects on antagonist action were found for point mutants of residues, F88A, D92A, F95A and F103A that were conserved or similar between sensitive/insensitive P2XR subtypes suggesting that these side chain interactions were not solely responsible for high affinity antagonist binding...
March 13, 2018: Molecular Pharmacology
Nurul Mubarokah, Julie-Ann Hulin, Peter Ian Mackenzie, Ross A McKinnon, Alex Z Haines, Dong Gui Hu, Robyn Meech
The UDP-glucuronosyltransferases (UGTs) of the gastrointestinal tract (GIT) have a crucial role in protection against dietary toxins and metabolism of orally administered drugs. A subset of UGTs including UGT1A8, UGT1A9, and UGT1A10 are highly expressed in GI tissues and this has been shown to be at least partly directed by the caudal homeodomain transcription factor, CDX2. We sought to further define the factors involved in regulation of the UGT1A8-1A10 genes and identified a novel composite element located within the proximal promoters of these three genes that binds to both CDX2 and the hepatocyte nuclear factor HNF4α, and mediates synergistic activation by these factors...
March 8, 2018: Molecular Pharmacology
Ragu Kanagasabai, Soumendrakrishna Karmahapatra, Corey A Kientz, Yang Yu, Victor A Hernandez, Evan E Kania, Terry S Elton, Jack C Yalowich
DNA topoisomerase IIα (170 kDa, TOP2α/170) is essential in proliferating cells by resolving DNA topological entanglements during chromosome condensation, replication, and segregation. We previously characterized a C-terminally truncated isoform (TOP2α/90), detectable in human leukemia K562 cells but more abundantly expressed in a clonal subline, K/VP.5, with acquired resistance to the anticancer agent etoposide. TOP2α/90 (786 aa) is the translation product of a TOP2α mRNA which retains a processed intron 19...
March 7, 2018: Molecular Pharmacology
Shane D Hellyer, Sabine Albold, Taide Wang, Amy Ny Chen, Lauren T May, Katie Leach, Karen J Gregory
Numerous positive and negative allosteric modulators (PAMs and NAMs) of Class C G protein-coupled receptors (GPCRs) have been developed as valuable preclinical pharmacological tools and therapeutic agents. While many Class C GPCR allosteric modulators have undergone subtype selectivity screening, most assay paradigms have failed to perform rigorous pharmacological assessment. Utilizing mGlu5 as a representative Class C GPCR, we tested the hypothesis that allosteric modulator selectivity was based on cooperativity rather than affinity...
March 7, 2018: Molecular Pharmacology
Feng Yi, Linda G Zachariassen, Katherine N Dorsett, Kasper B Hansen
NMDA-type glutamate receptors mediate excitatory synaptic transmission in the central nervous system and play critical roles in many neuronal processes. The physiological roles of NMDA receptors are shaped by their functional properties, which are highly dependent on subunit composition. Most NMDA receptors are assembled from two GluN1 and two GluN2 subunits, but diversity in subunit composition is made possible by eight GluN1 splice variants (i.e. isoforms) and four distinct GluN2 subunits (GluN2A-D). We demonstrate using FRET-FLIM that GluN1-1a and GluN1-1b isoforms, which includes or lacks residues encoded by exon 5, form triheteromeric GluN1-1a/GluN1-1b/GluN2A (1a/1b/2A) and GluN1-1a/GluN1-1b/GluN2B (1a/1b/2B) receptors...
February 26, 2018: Molecular Pharmacology
Hannah M Stoveken, Scott D Larsen, Alan V Smrcka, Gregory G Tall
Adhesion G protein-coupled receptors (aGPCRs) have emerged as potential therapeutic targets in multiple cancers and in neurological diseases. However, there are few modulatory compounds that act on these receptors. The majority of aGPCRs are orphans and a general activation mechanism has only recently been defined: aGPCRs are activated by a tethered agonist. aGPCRs constitutively cleave themselves during biosynthesis to generated two-part receptors comprised of an extracellular domain (ECD) and a 7-transmembrane spanning domain (7TM)...
February 23, 2018: Molecular Pharmacology
Guo Zhong, David Ortiz, Alex Zelter, Abhinav Nath, Nina Isoherranen
The clearance of retinoic acid (RA) and its metabolites is believed to be regulated by the CYP26 enzymes, but the specific roles of CYP26A1, CYP26B1 and CYP26C1 in clearing active vitamin A metabolites have not been defined. The goal of this study was to establish the substrate specificity of CYP26C1, and determine whether CYP26C1 interacts with cellular RA binding proteins (CRABPs). CYP26C1 was found to effectively metabolize all-trans- retinoic acid (atRA), 9-cis-retinoic acid (9-cis-RA), 13-cis-retinoic acid and 4-oxo-atRA with the highest intrinsic clearance towards 9-cis-RA...
February 23, 2018: Molecular Pharmacology
Taiming Liu, Meijuan Zhang, Michael H Terry, Hobe Schroeder, Sean Wilson, Gordon Power, Qian Li, Trent Tipple, Dan Borchardt, Arlin Blood
Glutathione-liganded binuclear dinitrosyl iron complex (glut-BDNIC) has been proposed to be a donor of nitric oxide (NO). This study was undertaken to investigate the mechanisms of vasoactivity, systemic hemodynamic effects, and pharmacokinetics of glut-BDNIC. To test the hypothesis that glut-BDNICs vasodilate by releasing NO in its reduced (HNO) state, a bioassay method of isolated, preconstricted ovine mesenteric arterial rings was used in the presence of selective scavengers of HNO or NO free radical (NO⋅), the vasodilatory effects of glut-BDNIC were found to have characteristics similar to those of an HNO donor and markedly different than a NO⋅ donor...
February 23, 2018: Molecular Pharmacology
Joanna C Jacob, Kensuke Sakakibara, Ryan A Mischel, Graeme Henderson, William L Dewey, Hamid I Akbarali
Oxycodone is a semi-synthetic opioid compound that is widely prescribed, used and abused today, and has a well-established role in shaping the current opioid epidemic. Previously we have shown that tolerance develops to the antinociceptive and respiratory depressive effects of oxycodone in mice, and that a moderate dose of acute ethanol or a PKC inhibitor reversed that tolerance. To investigate further if tolerance was occurring through neuronal mechanisms, our aims for this study were to assess the effects of acute and prolonged oxycodone in isolated dorsal root ganglia (DRG) neurons and to determine if this tolerance was reversed by either ethanol or a PKC inhibitor...
February 21, 2018: Molecular Pharmacology
Songqi Gao, Shirin Kahremany, Jianye Zhang, Beata Jastrzebska, Janice Querubin, Simon M Petersen-Jones, Krzysztof Palczewski
The retinoid (visual) cycle consists of a series of biochemical reactions needed to regenerate the visual chromophore, 11-cis-retinal and sustain vision. Genetic or environmental factors affecting chromophore production can lead to blindness. Using animal models that mimic human retinal diseases, we previously demonstrated that mechanism-based pharmacological interventions can maintain vision in otherwise incurable genetic diseases of the retina. Here, we report that after 9-cis-retinal administration to lecithin:retinol acyltransferase-deficient (Lrat-/-) mice, the drug was rapidly absorbed and then cleared within 1-2 h...
February 16, 2018: Molecular Pharmacology
Allison Germann, Daniel Shin, Christina Kuhrau, Alexander Johnson, Alex S Evers, Gustav Akk
GABAA receptors activated by the transmitter GABA are potentiated by several allosterically acting drugs including the intravenous anesthetic propofol. Propofol can also directly activate the receptor, albeit at higher concentrations. Previous functional studies have identified amino acid residues whose substitution reduces potentiation of GABA-activated receptors by propofol while enhancing the ability of propofol to directly activate the receptor. One interpretation of such observations is that the mutation has specific effects on the sites or processes involved in potentiation or activation...
February 8, 2018: Molecular Pharmacology
Anette Kaiser, Caroline Hempel, Lizzy Wanka, Mario Schubert, Heidi E Hamm, Annette G Beck-Sickinger
Ligand binding and pathway-specific activation of G protein-coupled receptors (GPCRs) is currently study with great effort. Individual answers may depend on the nature of the ligands and the effector pathway. Recently, we have presented a detailed model of NPY bound to the Y2R (Kaiser et al., 2015). Accordingly, the C-terminal part of the peptide binds deeply in the transmembrane bundle and brings the side chain of the most essential Y36in close proximity to W6.48Here, we investigate the role of this interaction for ligand binding and activation of this receptor...
February 7, 2018: Molecular Pharmacology
Mei-Hua Bao, Guang-Yi Li, Xiao-Shan Huang, Liang Tang, Li-Ping Dong, Jian-Ming Li
Angiogenesis in atherosclerotic plaque promotes plaque growth, causes plaque hemorrhage and violates plaque stability. LINC00657 is a long noncoding RNA highly conserved and abundantly expressed in vascular endothelial cells. The present study was designed to investigate the effects and mechanisms of LINC00675 on the low concentration of oxidized low-density lipoprotein (oxLDL) induced angiogenesis. Cell proliferation assay, transwell assay, wound healing assay, and tube formation assay were conducted to detect the effects of low concentration of oxLDL on angiogenesis; The results discovered that oxLDL promoted the cell proliferation, migration, and tube formation...
February 7, 2018: Molecular Pharmacology
J Albert Abrie, Wessel J A Moolman, Gyles E Cozier, Sylva L Schwager, K Ravi Acharya, Edward D Sturrock
Angiotensin-converting enzyme (ACE) plays a central role in the renin-angiotensin system (RAS), which is primarily responsible for blood pressure homeostasis. Studies have shown that ACE inhibitors yield cardiovascular benefits that cannot be entirely attributed to the inhibition of ACE catalytic activity. It is possible that these benefits are due to interactions between ACE and RAS receptors that mediate the protective arm of the RAS, such as the angiotensin-II receptor type 2 (AT2R) and the receptor MAS...
January 25, 2018: Molecular Pharmacology
Ryan S Wible, Quynh T Tran, Samreen Fathima, Carrie Hayes Sutter, Thomas W Kensler, Thomas R Sutter
The Keap1-Nrf2 signaling pathway is the subject of several clinical trials evaluating the effects of Nrf2 activation on the prevention of cancer, diabetes, and the treatment of chronic kidney disease and multiple sclerosis. 3H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two distinct series of Nrf2 chemical activators. Previous reports have described activator-specific effects on Nrf2-dependent gene regulation and physiological outcomes...
January 24, 2018: Molecular Pharmacology
Anita Nivedha, Christofer Tautermann, Supriyo Bhattacharya, Sangbae Lee, Paola Casarosa, Ines Kollak, Tobias Kiechle, Nagarajan Vaidehi
G-protein-coupled receptors (GPCRs) mediate multiple signaling pathways in the cell depending on the agonist that activates the receptor and multiple cellular factors. Agonists that show higher potency to specific signaling pathways over others are known as "biased agonists" and have been shown to have better therapeutic index. Although biased agonists are desirable, their design poses several challenges to date. The number of assays to identify biased agonists seems expensive and tedious. Therefore, computational methods that can reliably calculate the possible bias of various ligands ahead of experiments and provide guidance will be both cost and time effective...
January 24, 2018: Molecular Pharmacology
Bo Xu, Silvana Vasile, Soren Ostergaard, Johan F Paulsson, Jasna Pruner, Johan Aqvist, Birgitte S Wulff, Hugo Gutierrez-de-Teran, Dan Larhammar
Understanding the agonist-receptor interactions in the neuropeptide Y (NPY)/peptide YY (PYY) signaling system is fundamental for the design of novel modulators of appetite regulation. We report here a binding model for the native peptide agonist PYY to the human Y2 receptor based on computational and in vitro pharmacological analyses. The Molecular Dynamics (MD) simulations yielded a conserved binding orientation for the full PYY and five analogues truncated at the amino terminus, which were pharmacologically characterized...
January 24, 2018: Molecular Pharmacology
Jason M Booe, Margaret L Warner, Amanda M Roehrkasse, Debbie L Hay, Augen A Pioszak
Binding of the vasodilator peptides adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) to the class B GPCR calcitonin receptor-like receptor (CLR) is modulated by receptor activity-modifying proteins (RAMP). RAMP1 favors CGRP, whereas RAMP2 and RAMP3 favor AM. Crystal structures of peptide-bound RAMP1/2-CLR extracellular domain (ECD) heterodimers suggested RAMPs alter ligand preference through direct peptide contacts and allosteric modulation of CLR. Here, we probed this dual mechanism through rational structure-guided design of AM and CGRP antagonist variants...
January 23, 2018: Molecular Pharmacology
Marissa Opelt, Gerald Wolkart, Emrah Eroglu, Markus Waldeck-Weiermair, Roland Malli, Wolfgang F Graier, Alexander Kollau, John T Fassett, Astrid Schrammel, Bernd Mayer, Antonius C F Gorren
According to current views, oxidation of aldehyde dehydrogenase-2 (ALDH2) in the course of glyceryltrinitrate (GTN) biotransformation is essentially involved in vascular nitrate tolerance and explains the dependence of the reaction on added thiols. Using a novel fluorescent intracellular NO probe expressed in vascular smooth muscle cells (VSMC) we observed ALDH2-catalyzed formation of nitric oxide (NO) from GTN in the presence of exogenously added dithiothreitol (DTT), whereas only a short burst of NO, corresponding to a single turnover of ALDH2, occurred in the absence of DTT...
January 22, 2018: Molecular Pharmacology
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