496 results on '"van der Stelt, Mario"'
Search Results
152. Discovery of Glycine Sulfonamides as Dual Inhibitors of sn-1-Diacylglycerol Lipase α and α/β-Hydrolase Domain 6
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Janssen, Freek J., primary, Deng, Hui, additional, Baggelaar, Marc P., additional, Allarà, Marco, additional, van der Wel, Tom, additional, den Dulk, Hans, additional, Ligresti, Alessia, additional, van Esbroeck, Annelot C. M., additional, McGuire, Ross, additional, Di Marzo, Vincenzo, additional, Overkleeft, Herman S., additional, and van der Stelt, Mario, additional
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- 2014
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153. Structure-Based Design of β1i or β5i Specific Inhibitors of Human Immunoproteasomes
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de Bruin, Gerjan, primary, Huber, Eva M., additional, Xin, Bo-Tao, additional, van Rooden, Eva J., additional, Al-Ayed, Karol, additional, Kim, Kyung-Bo, additional, Kisselev, Alexei F., additional, Driessen, Christoph, additional, van der Stelt, Mario, additional, van der Marel, Gijsbert A., additional, Groll, Michael, additional, and Overkleeft, Herman S., additional
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- 2014
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154. Inside Back Cover: Development of an Activity-Based Probe and In Silico Design Reveal Highly Selective Inhibitors for Diacylglycerol Lipase-α in Brain (Angew. Chem. Int. Ed. 46/2013)
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Baggelaar, Marc P., primary, Janssen, Freek J., additional, van Esbroeck, Annelot C. M., additional, den Dulk, Hans, additional, Allarà, Marco, additional, Hoogendoorn, Sascha, additional, McGuire, Ross, additional, Florea, Bogdan I., additional, Meeuwenoord, Nico, additional, van den Elst, Hans, additional, van der Marel, Gijsbert A., additional, Brouwer, Jaap, additional, Di Marzo, Vincenzo, additional, Overkleeft, Herman S., additional, and van der Stelt, Mario, additional
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- 2013
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155. Innenrücktitelbild: Development of an Activity-Based Probe and In Silico Design Reveal Highly Selective Inhibitors for Diacylglycerol Lipase-α in Brain (Angew. Chem. 46/2013)
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Baggelaar, Marc P., primary, Janssen, Freek J., additional, van Esbroeck, Annelot C. M., additional, den Dulk, Hans, additional, Allarà, Marco, additional, Hoogendoorn, Sascha, additional, McGuire, Ross, additional, Florea, Bogdan I., additional, Meeuwenoord, Nico, additional, van den Elst, Hans, additional, van der Marel, Gijsbert A., additional, Brouwer, Jaap, additional, Di Marzo, Vincenzo, additional, Overkleeft, Herman S., additional, and van der Stelt, Mario, additional
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- 2013
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156. Development of an Activity-Based Probe and In Silico Design Reveal Highly Selective Inhibitors for Diacylglycerol Lipase-α in Brain
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Baggelaar, Marc P., primary, Janssen, Freek J., additional, van Esbroeck, Annelot C. M., additional, den Dulk, Hans, additional, Allarà, Marco, additional, Hoogendoorn, Sascha, additional, McGuire, Ross, additional, Florea, Bogdan I., additional, Meeuwenoord, Nico, additional, van den Elst, Hans, additional, van der Marel, Gijsbert A., additional, Brouwer, Jaap, additional, Di Marzo, Vincenzo, additional, Overkleeft, Herman S., additional, and van der Stelt, Mario, additional
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- 2013
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157. Incorporation of Non-natural Amino Acids Improves Cell Permeability and Potency of Specific Inhibitors of Proteasome Trypsin-like Sites
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Geurink, Paul P., primary, van der Linden, Wouter A., additional, Mirabella, Anne C., additional, Gallastegui, Nerea, additional, de Bruin, Gerjan, additional, Blom, Annet E. M., additional, Voges, Mathias J., additional, Mock, Elliot D., additional, Florea, Bogdan I., additional, van der Marel, Gijs A., additional, Driessen, Christoph, additional, van der Stelt, Mario, additional, Groll, Michael, additional, Overkleeft, Herman S., additional, and Kisselev, Alexei F., additional
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- 2013
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158. A Set of Activity-Based Probes to Visualize Human (Immuno)proteasome Activities.
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de Bruin, Gerjan, Xin, Bo Tao, Kraus, Marianne, van der Stelt, Mario, van der Marel, Gijsbert A., Kisselev, Alexei F., Driessen, Christoph, Florea, Bogdan I., and Overkleeft, Herman S.
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PROTEASOME inhibitors ,ANTINEOPLASTIC agent synthesis ,LYMPHOBLASTIC leukemia treatment ,FLUORESCENT probes ,BINDING sites - Abstract
Proteasomes are therapeutic targets for various cancers and autoimmune diseases. Constitutively expressed proteasomes have three active sites, β1c, β2c, and β5c. Lymphoid tissues also express the immunoproteasome subunits β1i, β2i, and β5i. Rapid and simultaneous measurement of the activity of these catalytic subunits would assist in the discovery of new inhibitors, improve analysis of proteasome inhibitors in clinical trials, and simplify analysis of subunit expression. In this work, we present a cocktail of activity-based probes that enables simultaneous gel-based detection of all six catalytic human proteasome subunits. We used this cocktail to develop specific inhibitors for β1c, β2c, β5c, and β2i, to compare the active-site specificity of clinical proteasome inhibitors, and to demonstrate that many hematologic malignancies predominantly express immunoproteasomes. Furthermore, we show that selective and complete inhibition of β5i and β1i is cytotoxic to primary cells from acute lymphocytic leukemia (ALL) patients. [ABSTRACT FROM AUTHOR]
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- 2016
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159. Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition.
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Daisuke Ogasawara, Hui Deng, Viader, Andreu, Baggelaar, Marc P., Breman, Arjen, den Dulk, Hans, van den Nieuwendijk, Adriann M. C. H., Soethoudt, Marjolein, van der Wel, Tom, Juan Zhou, Overkleeft, Herman S., Sanchez-Alavez, Manuel, Mo, Simone, Nguyen, William, Conti, Bruno, Xiaojie Liu, Yao Chen, Qing-song Liu, Cravatt, Benjamin F., and van der Stelt, Mario
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DIGLYCERIDES ,LIPASES ,CANNABINOID receptors ,LIPOPOLYSACCHARIDES ,CENTRAL nervous system ,NEUROPLASTICITY - Abstract
Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLα is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network. [ABSTRACT FROM AUTHOR]
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- 2016
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160. Comprehensive Analysis of Structure-Activity Relationships of a-Ketoheterocycles as sn-1-Diacylglycerol Lipase a Inhibitors.
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Janssen, Freek J., Baggelaar, Marc P., Hummel, Jessica J. A., Overkleeft, Herman S., Cravatt, Benjamin F., Boger, Dale L., and van der Stelt, Mario
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- 2015
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161. A Novel Selective Inverse Agonist of the CB2Receptor as a Radiolabeled Tool Compound for Kinetic Binding Studies
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Martella, Andrea, Sijben, Huub, Rufer, Arne C., Grether, Uwe, Fingerle, Juergen, Ullmer, Christoph, Hartung, Thomas, IJzerman, Adriaan P., van der Stelt, Mario, and Heitman, Laura H.
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The endocannabinoid system, and in particular the cannabinoid type 2 receptor (CB2R), raised the interest of many medicinal chemistry programs for its therapeutic relevance in several (patho)physiologic processes. However, the physico-chemical properties of tool compounds for CB2R (e.g., the radioligand [3H]CP55,940) are not optimal, despite the research efforts in developing effective drugs to target this system. At the same time, the importance of drug-target binding kinetics is growing since the kinetic binding profile of a ligand may provide important insights for the resulting in vivo efficacy. In this context we synthesized and characterized [3H]RO6957022, a highly selective CB2R inverse agonist, as a radiolabeled tool compound. In equilibrium and kinetic binding experiments [3H]RO6957022 showed high affinity for human CB2R with fast association (kon) and moderate dissociation (koff) kinetics. To demonstrate the robustness of [3H]RO6957022 binding, affinity studies were carried out for a wide range of CB2R reference ligands, spanning the range of full, partial, and inverse agonists. Finally, we used [3H]RO6957022 to study the kinetic binding profiles (i.e., konand koffvalues) of selected synthetic and endogenous (i.e., 2-arachidonoylglycerol, anandamide, and noladin ether) CB2R ligands by competition association experiments. All tested ligands, and in particular the endocannabinoids, displayed distinct kinetic profiles, shedding more light on their mechanism of action and the importance of association rates in the determination of CB2R affinity. Altogether, this study shows that the use of a novel tool compound, i.e., [3H]RO6957022, can support the development of novel ligands with a repertoire of kinetic binding profiles for CB2R.
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- 2017
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162. Discovery and Optimization of 1-(4-(Pyridin-2-yl)benzyl)imidazolidine-2,4-dione Derivatives As a Novel Class of Selective Cannabinoid CB2 Receptor Agonists
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van der Stelt, Mario, primary, Cals, Jos, additional, Broeders-Josten, Silvia, additional, Cottney, Jean, additional, van der Doelen, Antoon A., additional, Hermkens, Marcel, additional, de Kimpe, Vera, additional, King, Angela, additional, Klomp, Jan, additional, Oosterom, Julia, additional, Pols-de Rooij, Ilse, additional, de Roos, Jeroen, additional, van Tilborg, Martin, additional, Boyce, Susan, additional, and Baker, James, additional
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- 2011
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163. Discovery of Novel Small Molecule Activators of β-Catenin Signaling
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Verkaar, Folkert, primary, van der Stelt, Mario, additional, Blankesteijn, W. Matthijs, additional, van der Doelen, Antoon A., additional, and Zaman, Guido J. R., additional
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- 2011
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164. Identification and Developmentof Biphenyl SubstitutedIminosugars as Improved Dual Glucosylceramide Synthase/Neutral GlucosylceramidaseInhibitors.
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Ghisaidoobe, Amar T., van den Berg, Richard J. B. H. N., Butt, Saleem S., Strijland, Anneke, Donker-Koopman, Wilma E., Scheij, Saskia, van den Nieuwendijk, Adrianus M. C. H., Koomen, Gerrit-Jan, van Loevezijn, Arnold, Leemhuis, Mark, Wennekes, Tom, van der Stelt, Mario, van der Marel, Gijsbert A., van Boeckel, Constant A. A., Aerts, Johannes M. F. G., and Overkleeft, Herman S.
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- 2014
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165. Forebrain-Specific Inactivation of Gq/G11 Family G Proteins Results in Age-Dependent Epilepsy and Impaired Endocannabinoid Formation
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Wettschureck, Nina, primary, van der Stelt, Mario, additional, Tsubokawa, Hiroshi, additional, Krestel, Heinz, additional, Moers, Alexandra, additional, Petrosino, Stefania, additional, Schütz, Günther, additional, Di Marzo, Vincenzo, additional, and Offermanns, Stefan, additional
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- 2006
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166. N-Arachidonoyl-Dopamine Tunes Synaptic Transmission onto Dopaminergic Neurons by Activating both Cannabinoid and Vanilloid Receptors
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Marinelli, Silvia, primary, Di Marzo, Vincenzo, additional, Florenzano, Fulvio, additional, Fezza, Filomena, additional, Viscomi, Maria Teresa, additional, van der Stelt, Mario, additional, Bernardi, Giorgio, additional, Molinari, Marco, additional, Maccarrone, Mauro, additional, and Mercuri, Nicola B, additional
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- 2006
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167. Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels
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van der Stelt, Mario, primary, Trevisani, Marcello, additional, Vellani, Vittorio, additional, De Petrocellis, Luciano, additional, Schiano Moriello, Aniello, additional, Campi, Barbara, additional, McNaughton, Peter, additional, Geppetti, Piero, additional, and Di Marzo, Vincenzo, additional
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- 2005
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168. Further evidence for the existence of a specific process for the membrane transport of anandamide
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LIGRESTI, Alessia, primary, MORERA, Enrico, additional, van der STELT, Mario, additional, MONORY, Krisztina, additional, LUTZ, Beat, additional, ORTAR, Giorgio, additional, and Di MARZO, Vincenzo, additional
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- 2004
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169. Oxygenated Metabolites of Anandamide and 2-Arachidonoylglycerol: Conformational Analysis and Interaction with Cannabinoid Receptors, Membrane Transporter, and Fatty Acid Amide Hydrolase
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van der Stelt, Mario, primary, van Kuik, J. Albert, additional, Bari, Monica, additional, van Zadelhoff, Guus, additional, Leeflang, Bas R., additional, Veldink, Gerrit A., additional, Finazzi-Agrò, Alessandro, additional, Vliegenthart, Johannes F. G., additional, and Maccarrone, Mauro, additional
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- 2002
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170. N-Tetradecylcarbamyl Lipopeptidesas Novel Agonists for Toll-like Receptor 2.
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Willems, Marian M. J. H. P., Zom, Gijs G., Khan, Selina, Meeuwenoord, Nico, Melief, Cornelis J. M., van der Stelt, Mario, Overkleeft, Herman S., Codée, Jeroen D. C., vander Marel, Gijsbert A., Ossendorp, Ferry, and Filippov, Dmitri V.
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- 2014
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171. Discovery of Glycine Sulfonamidesas Dual Inhibitorsof sn-1-Diacylglycerol Lipase α and α/β-HydrolaseDomain 6.
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Janssen, Freek J., Deng, Hui, Baggelaar, Marc P., Allarà, Marco, van der Wel, Tom, den Dulk, Hans, Ligresti, Alessia, van Esbroeck, Annelot C. M., McGuire, Ross, Di Marzo, Vincenzo, Overkleeft, Herman S., and van der Stelt, Mario
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- 2014
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172. Structure-Based Design ofβ1i or β5i SpecificInhibitors of Human Immunoproteasomes.
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de Bruin, Gerjan, Huber, Eva M., Xin, Bo-Tao, van Rooden, Eva J., Al-Ayed, Karol, Kim, Kyung-Bo, Kisselev, Alexei F., Driessen, Christoph, van der Stelt, Mario, vander Marel, Gijsbert A., Groll, Michael, and Overkleeft, Herman S.
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- 2014
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173. Incorporation of Non-naturalAmino Acids ImprovesCell Permeability and Potency of Specific Inhibitors of ProteasomeTrypsin-like Sites.
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Geurink, Paul P., van der Linden, Wouter A., Mirabella, Anne C., Gallastegui, Nerea, de Bruin, Gerjan, Blom, Annet E. M., Voges, Mathias J., Mock, Elliot D., Florea, Bogdan I., van derMarel, Gijs A., Driessen, Christoph, van der Stelt, Mario, Groll, Michael, Overkleeft, Herman S., and Kisselev, Alexei F.
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- 2013
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174. Understanding and Targeting the Endocannabinoid System with Activity‐Based Protein Profiling.
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Zhu, Na, Janssen, Antonius P. A., and van der Stelt, Mario
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CANNABINOID receptors , *SMALL molecules , *PROTEINS , *NEUROPLASTICITY , *NEURAL development , *CANNABINOIDS - Abstract
The endocannabinoid system (ECS) is a widespread modulatory system composed of cannabinoid receptors, endogenous signaling lipids termed endocannabinoids and the enzymes for the biosynthesis and degradation of these endocannabinoids. It plays a crucial role in diverse (patho)physiological functions, such as neurotransmission, neural development, synaptic plasticity, mood, food intake, and inflammation. Enzymes involved in the biosynthesis (e. g. NAPE‐PLD, DAGLs) and degradation (e. g. FAAH, MAGL) of endocannabinoids have attracted attention from both academia and industry due to their therapeutic potential. The discovery of selective inhibitors for these enzymes is important for functional assignment and biomedical applications. Activity‐based protein profiling (ABPP) has emerged as a powerful technique, which to a large extend accelerated the development of selective inhibitors for ECS enzymes. This review summarizes the representative activity‐based probes (ABPs) and small molecular inhibitors developed in the past two decades for ECS enzymes and will discuss the biological discoveries attributed by the application of these small molecules. [ABSTRACT FROM AUTHOR]
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- 2023
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175. The role of the CB1 cannabinoid receptor and its endogenous ligands, anandamide and 2-arachidonoylglycerol, in amphetamine-induced behavioural sensitization
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Thiemann, Gunnar, van der Stelt, Mario, Petrosino, Stefania, Molleman, Areles, Di Marzo, Vincenzo, and Hasenöhrl, Rüdiger U.
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HUMAN behavior , *RODENTS , *LOCAL anesthetics , *NEUROTRANSMITTER receptors - Abstract
Abstract: Cannabinoid receptors and their endogenous ligands (endocannabinoids) have been implicated in cocaine and amphetamine reward. Their role in psychostimulant-induced behavioural sensitization still has to be determined. The purpose of the present study was, for one, to compare the effects of a pharmacological and genetic manipulation of CB1 cannabinoid receptors on amphetamine-induced locomotor sensitization in mice, and, secondly, to quantify the concentration of anandamide and 2-arachidonoylglycerol in different forebrain areas of behaviourally sensitized animals. The results can be summarized as follows: CB1 knockout mice failed to sensitize to the locomotor stimulant effects of amphetamine. On the contrary, administration of the CB1 receptor antagonist SR141716A (rimonabant; 3mg/kg; i.p.) increased amphetamine sensitization in wild-type animals, indicating that the difference between CB1 knockouts and SR141716A treated animals could be due to the ‘chronic’ versus ‘acute’ loss of CB1 receptor function, or, alternatively, that SR141716A could exert pharmacological effects beyond its proposed CB1 antagonistic action. Furthermore, sensitized wild-type mice and animals, which had received a single amphetamine injection on the challenge day, both had increased anandamide concentrations in the dorsal striatum and decreased anandamide levels in the ventral striatum, comprising nucleus accumbens. 2-Arachidonoylglycerol levels were decreased in the ventral striatum of sensitized animals only. Together, these findings suggest that prolonged activation of dopamine receptors could alter endocannabinoid levels and support the proposed involvement of the CB1 receptor in amphetamine sensitization. [Copyright &y& Elsevier]
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- 2008
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176. N-Arachidonoyl-Dopamine Tunes Synaptic Transmission onto Dopaminergic Neurons by Activating both Cannabinoid and Vanilloid Receptors.
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Marinelli, Silvia, Di Marzo, Vincenzo, Florenzano, Fulvio, Fezza, Filomena, Viscomi, Maria Teresa, van der Stelt, Mario, Bernardi, Giorgio, Molinari, Marco, Maccarrone, Mauro, and Mercuri, Nicola B.
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CANNABINOIDS ,PATCH-clamp techniques (Electrophysiology) ,CHROMATOGRAPHIC analysis ,NEURAL transmission ,CONFOCAL microscopy - Abstract
In the present study, we used electrophysiological, biochemical, and confocal microscopy techniques, to investigate the functional role of transient receptor potential vanilloid type 1 (TRPV1) and cannabinoid type 1 receptors (CB1-R) in the substantia nigra pars compacta (SNpc) and their stimulation by the endocannabinoid N-arachidonoyl-dopamine (NADA). Liquid chromatography–mass spectrometry analyses revealed that a NADA-like compound is produced in substantia nigra slices, in conditions of hyperactivity. Moreover, the functional role of both TRPV1 and CB1-R in modulating synaptic transmission in this area was suggested by confocal microscopy data, showing TRPV1 and CB1-R immunoreactivity in punctate structures, probably representing synaptic contacts on cell bodies of the SNpc. In patch-clamp recordings from dopamine (DA) neurons of the SNpc, we found that NADA increases or reduces glutamatergic transmission onto DA neurons by activating TRPV1 and CB1 receptors, respectively, whereas it decreases GABAergic transmission via CB1 stimulation. Facilitation of glutamate release through TRPV1 was blocked in the presence of a selective blocker of the putative endocannabinoid membrane transporter (EMT), indicating that NADA needs to be taken up by cells to interact with this receptor. In line with these data, biochemical results demonstrated that NADA selectively acted at CB1-R when its re-uptake was blocked. Altogether these data demonstrate a significant role exerted by the endocannabinoid/endovanilloid NADA in the regulation of synaptic transmission to DA neurons of the SNpc. Moreover, they highlight a key function of the EMT transporter in promoting the stimulation of TRPV1 or CB1-R, thus favoring facilitation or inhibition of glutamate synaptic release.Neuropsychopharmacology (2007) 32, 298–308. doi:10.1038/sj.npp.1301118; published online 7 June 2006 [ABSTRACT FROM AUTHOR]
- Published
- 2007
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177. Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels.
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van der Stelt, Mario, Trevisani, Marcello, Vellani, Vittorio, De Petrocellis, Luciano, Moriello, Aniello Schiano, Campi, Barbara, McNaughton, Peter, Geppetti, Piero, and Di Marzo, Vincenzo
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PURINERGIC receptors , *MUSCARINIC receptors , *SENSORY neurons , *GENE transfection , *NEURONS , *PHOSPHOLIPASES - Abstract
The endocannabinoid anandamide is able to interact with the transient receptor potential vanilloid 1 (TRPV1) channels at a molecular level. As yet, endogenously produced anandamide has not been shown to activate TRPV1, but this is of importance to understand the physiological function of this interaction. Here, we show that intracellular Ca2+ mobilization via the purinergic receptor agonist ATP, the muscarinic receptor agonist carbachol or the Ca2+-ATPase inhibitor thapsigargin leads to formation of anandamide, and subsequent TRPV1-dependent Ca2+ influx in transfected cells and sensory neurons of rat dorsal root ganglia (DRG). Anandamide metabolism and efflux from the cell tonically limit TRPV1-mediated Ca2+ entry. In DRG neurons, this mechanism was found to lead to TRPV1-mediated currents that were enhanced by selective blockade of anandamide cellular efflux. Thus, endogenous anandamide is formed on stimulation of metabotropic receptors coupled to the phospholipase C/inositol 1,4,5-triphosphate pathway and then signals to TRPV1 channels. This novel intracellular function of anandamide may precede its action at cannabinoid receptors, and might be relevant to its control over neurotransmitter release. [ABSTRACT FROM AUTHOR]
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- 2005
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178. Endovanilloids.
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van der Stelt, Mario and Di Marzo, Vincenzo
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TRP channels , *MEMBRANE proteins , *CAPSAICIN , *ARACHIDONIC acid , *CANNABINOIDS , *LIPIDS , *CELLULAR signal transduction , *LIGANDS (Biochemistry) - Abstract
Endovanilloids are defined as endogenous ligands of the transient receptor potential vanilloid type 1 (TRPV1) protein, a nonselective cation channel that belongs to the large family of TRP ion channels, and is activated by the pungent ingredient of hot chilli peppers, capsaicin. TRPV1 is expressed in some nociceptor efferent neurons, where it acts as a molecular sensor of noxious heat and low pH. However, the presence of these channels in various regions of the central nervous system, where they are not likely to be targeted by these noxious stimuli, suggests the existence of endovanilloids. Three different classes of endogenous lipids have been found recently that can activate TRPV1, i.e. unsaturated N-acyldopamines, lipoxygenase products of arachidonic acid and the endocannabinoid anandamide with some of its congeners. To classify a molecule as an endovanilloid, the compound should be formed or released in an activity-dependent manner in sufficient amounts to evoke a TRPV1-mediated response by direct activation of the channel. To control TRPV1 signaling, endovanilloids should be inactivated within a short time-span. In this review, we will discuss, for each of the proposed endogenous ligands of TRPV1, their ability to act as endovanilloids in light of the criteria mentioned above. [ABSTRACT FROM AUTHOR]
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- 2004
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179. In Vivo Excitotoxicity Induced by Ouabain, a Na+/K+-ATPase Inhibitor.
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Veldhuis, Wouter B, van der Stelt, Mario, Delmas, Florence, Gillet, Brigitte, Veldink, Gerrit A, Vliegenthart, Johannes F G, Nicolay, Klaas, and Bär, Peter R
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- 2003
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180. Chemical Probes to Control and Visualize Lipid Metabolism in the Brain
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Punt, Jeroen M., van der Vliet, Daan, and van der Stelt, Mario
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Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological processes, including pain sensation, appetite, memory formation, stress, and anxiety. Unlike classical neurotransmitters, lipid messengers are produced on demand and degraded by metabolic enzymes to control their lifespan and signaling actions. Chemical biology approaches have become one of the main driving forces to study and unravel the physiological role of lipid messengers in the brain. Here, we review how the development and use of chemical probes has allowed one to study endocannabinoid signaling by (i) inhibiting the biosynthetic and metabolic enzymes; (ii) visualizing the activity of these enzymes; and (iii) controlling the release and transport of the endocannabinoids. Activity-based probes were instrumental to guide the discovery of highly selective and in vivo active inhibitors of the biosynthetic (DAGL, NAPE-PLD) and metabolic (MAGL, FAAH) enzymes of endocannabinoids. These inhibitors allowed one to study the role of these enzymes in animal models of disease. For instance, the DAGL–MAGL axis was shown to control neuroinflammation and the NAPE-PLD–FAAH axis to regulate emotional behavior. Activity-based protein profiling and chemical proteomics were essential to guide the drug discovery and development of compounds targeting MAGL and FAAH, such as ABX-1431 (Lu AG06466) and PF-04457845, respectively. These experimental drugs are now in clinical trials for multiple indications, including multiple sclerosis and post-traumatic stress disorders. Activity-based probes have also been used to visualize the activity of these lipid metabolizing enzymes with high spatial resolution in brain slices, thereby showing the cell type-specific activity of these lipid metabolizing enzymes. The transport, release, and uptake of signaling lipids themselves cannot, however, be captured by activity-based probes in a spatiotemporal controlled manner. Therefore, bio-orthogonal lipids equipped with photoreactive, photoswitchable groups or photocages have been developed. These chemical probes were employed to investigate the protein interaction partners of the endocannabinoids, such as putative membrane transporters, as well as to study the functional cellular responses within milliseconds upon irradiation. Finally, genetically encoded sensors have recently been developed to monitor the real-time release of endocannabinoids with high spatiotemporal resolution in cultured neurons, acute brain slices, and in vivo mouse models. It is anticipated that the combination of chemical probes, highly selective inhibitors, and sensors with advanced (super resolution) imaging modalities, such as PharmacoSTORM and correlative light-electron microscopy, will uncover the fundamental basis of lipid signaling at nanoscale resolution in the brain. Furthermore, chemical biology approaches enable the translation of these fundamental discoveries into clinical solutions for brain diseases with aberrant lipid signaling.
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- 2022
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181. Comparative Photoaffinity Profiling of Omega-3 Signaling Lipid Probes Reveals Prostaglandin Reductase 1 as a Metabolic Hub in Human Macrophages
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Gagestein, Berend, von Hegedus, Johannes H., Kwekkeboom, Joanneke C., Heijink, Marieke, Blomberg, Niek, van der Wel, Tom, Florea, Bogdan I., van den Elst, Hans, Wals, Kim, Overkleeft, Herman S., Giera, Martin, Toes, René E. M., Ioan-Facsinay, Andreea, and van der Stelt, Mario
- Abstract
The fish oil constituent docosahexaenoic acid (DHA, 22:6 n-3) is a signaling lipid with anti-inflammatory properties. The molecular mechanisms underlying the biological effect of DHA are poorly understood. Here, we report the design, synthesis, and application of a complementary pair of bio-orthogonal, photoreactive probes based on the polyunsaturated scaffold DHA and its oxidative metabolite 17-hydroxydocosahexaenoic acid (17-HDHA). In these probes, an alkyne serves as a handle to introduce a fluorescent reporter group or a biotin-affinity tag via copper(I)-catalyzed azide-alkyne cycloaddition. This pair of chemical probes was used to map specific targets of the omega-3 signaling lipids in primary human macrophages. Prostaglandin reductase 1 (PTGR1) was identified as an interaction partner that metabolizes 17-oxo-DHA, an oxidative metabolite of 17-HDHA. 17-oxo-DHA reduced the formation of pro-inflammatory lipids 5-HETE and LTB4 in human macrophages and neutrophils. Our results demonstrate the potential of comparative photoaffinity protein profiling for the discovery of metabolic enzymes of bioactive lipids and highlight the power of chemical proteomics to uncover new biological insights.
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- 2022
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182. Chemical Proteomics Reveals Off-Targets of the Anandamide Reuptake Inhibitor WOBE437
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Gagestein, Berend, Stevens, Anna F., Fazio, Domenico, Florea, Bogdan I., van der Wel, Tom, Bakker, Alexander T., Fezza, Filomena, Dulk, Hans den, Overkleeft, Herman S., Maccarrone, Mauro, and van der Stelt, Mario
- Abstract
Anandamide or N-arachidonoylethanolamine (AEA) is a signaling lipid that modulates neurotransmitter release via activation of the type 1 cannabinoid receptor (CB1R) in the brain. Termination of anandamide signaling is thought to be mediated viaa facilitated cellular reuptake process that utilizes a purported transporter protein. Recently, WOBE437 has been reported as a novel, natural product-based inhibitor of AEA reuptake that is active in cellular and in vivomodels. To profile its target interaction landscape, we synthesized pac-WOBE, a photoactivatable probe derivative of WOBE437, and performed chemical proteomics in mouse neuroblastoma Neuro-2a cells. Surprisingly WOBE437, unlike the widely used selective inhibitor of AEA uptake OMDM-1, was found to increase AEA uptake in Neuro-2a cells. In line with this, WOBE437 reduced the cellular levels of AEA and related N-acylethanolamines (NAEs). Using pac-WOBE, we identified saccharopine dehydrogenase-like oxidoreductase (SCCPDH), vesicle amine transport 1 (VAT1), and ferrochelatase (FECH) as WOBE437-interacting proteins in Neuro-2a cells. Further genetic studies indicated that SCCPDH and VAT1 were not responsible for the WOBE437-induced reduction in NAE levels. Regardless of the precise mechanism of action of WOB437 in AEA transport, we have identified SSCPHD, VAT1, and FECH as unprecedented off-targets of this molecule which should be taken into account when interpreting its cellular and in vivoeffects.
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- 2022
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183. P2X7 receptor‐dependent increase in endocannabinoid 2‐arachidonoyl glycerol production by neuronal cells in culture: Dynamics and mechanism.
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Singh, Simar, Sarroza, Dennis, English, Anthony, Whittington, Dale, Dong, Ao, Malamas, Michael, Makriyannis, Alexandros, van der Stelt, Mario, Li, Yulong, Zweifel, Larry, Bruchas, Michael R., Land, Benjamin B., and Stella, Nephi
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CANNABINOID receptors , *CELL culture , *CONFOCAL fluorescence microscopy , *PHOSPHOLIPASE C , *GLYCERIN , *NEUROLOGICAL disorders - Abstract
Background and Purpose: Neurotransmission and neuroinflammation are controlled by local increases in both extracellular ATP and the endocannabinoid 2‐arachidonoyl glycerol (2‐AG). While it is known that extracellular ATP stimulates 2‐AG production in cells in culture, the dynamics and molecular mechanisms that underlie this response remain poorly understood. Detection of real‐time changes in eCB levels with the genetically encoded sensor, GRABeCB2.0, can address this shortfall. Experimental Approach: 2‐AG and arachidonoylethanolamide (AEA) levels in Neuro2a (N2a) cells were measured by LC‐MS, and GRABeCB2.0 fluorescence changes were detected using live‐cell confocal microscopy and a 96‐well fluorescence plate reader. Key Results: 2‐AG and AEA increased GRABeCB2.0 fluorescence in N2a cells with EC50 values of 81 and 58 nM, respectively; both responses were reduced by the cannabinoid receptor type 1 (CB1R) antagonist SR141617 and absent in cells expressing the mutant‐GRABeCB2.0. ATP increased only 2‐AG levels in N2a cells, as measured by LC‐MS, and induced a transient increase in the GRABeCB2.0 signal within minutes primarily via activation of P2X7 receptors (P2X7R). This response was dependent on diacylglycerol lipase β activity, partially dependent on extracellular calcium and phospholipase C activity, but not controlled by the 2‐AG hydrolysing enzyme, α/β‐hydrolase domain containing 6 (ABHD6). Conclusions and Implications: Considering that P2X7R activation increases 2‐AG levels within minutes, our results show how these molecular components are mechanistically linked. The specific molecular components in these signalling systems represent potential therapeutic targets for the treatment of neurological diseases, such as chronic pain, that involve dysregulated neurotransmission and neuroinflammation. [ABSTRACT FROM AUTHOR]
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- 2024
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184. Discovery of a Cannabinoid CB2 Receptor Fluorescent Probe Based on a Pyridin-2-yl-benzyl-imidazolidine-2,4-dione Scaffold.
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de Paus, Laura V., Janssen, Antonius P.A., Halimi, Asad, van den Berg, Richard J. B. H. N., Heitman, Laura H., and van der Stelt, Mario
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FLUORESCENT probes , *CANNABINOID receptors , *MOLECULES , *G protein coupled receptors , *AMINATION , *LIFE sciences - Abstract
This document discusses the development of a fluorescent probe, called compound 22, for the cannabinoid CB2 receptor. The probe was designed to visualize the receptor without the need for a toxic copper-mediated reaction. It demonstrated reasonable affinity for the CB2 receptor, selectivity over the CB1 receptor, and acted as an inverse agonist. The study also highlights the potential impact of small structural changes in compounds on the functional behavior of the CB2 receptor. This research contributes to the development of CB2 receptor-selective drugs for various applications. [Extracted from the article]
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- 2024
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185. In VivoExcitotoxicity Induced by Ouabain, a Na+/K+-ATPase Inhibitor
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Veldhuis, Wouter B., van der Stelt, Mario, Delmas, Florence, Gillet, Brigitte, Veldink, Gerrit A., Vliegenthart, Johannes F. G., Nicolay, Klaas, and Bär, Peter R.
- Abstract
The susceptibility of immature rat brain to neurotoxicity of N-methyl-D-aspartate (NMDA) has provided a widely used in vivoparadigm to study excitotoxicity relevant to acute neurodegenerative diseases such as cerebral ischemia. In this study, in vivoexcitotoxicity was induced via injection of ouabain (1 mM/0.5 μL), a Na+/K+-ATPase-inhibitor, into neonatal rat brain and compared with NMDA injection. The aim of the study was to induce excitotoxicity secondary to cellular membrane depolarization, thereby more closely mimicking the pathophysiologic processes of ischemia-induced brain injury where NMDA-receptor overstimulation by glutamate follows, not precedes, membrane depolarization. Na+/K+-ATPase-inhibition caused an acute, 40% ± 8% decrease of the apparent diffusion coefficient (ADC) of water, as measured using diffusion-weighted magnetic resonance imaging (MRI), and resulted in infarctlike lesions as measured using T2-weighted MRI and histology up to 2 weeks later. Localized one- and two-dimensional 1H-magnetic resonance spectroscopy (MRS) demonstrated that the early excitotoxic diffusion changes were not accompanied by an overall metabolic disturbance. Furthermore, 31P-MRS demonstrated that energy depletion is not a prerequisite for ADC decrease or excitotoxic cell death. Treatment with the NMDA-antagonist MK-80 (1 mg/kg) attenuated the volume of tissue exhibiting a decreased ADC (P< 0.005), demonstrating that the ouabain-induced injury is indeed excitotoxic in nature. The authors argue that, compared with NMDA-injection, ouabain-induced excitotoxicity elicits more appropriate glutamate-receptor overstimulation and is better suited to detect relevant neuroprotection in that it is more sensitive to attenuation of synaptic glutamate levels.
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- 2003
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186. A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson's disease.
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Van der Stelt, Mario, Fox, Susan H., Hill, Michael, Crossman, Alan R., Petrosino, Stefania, Di Marzo, Vincenzo, and Brotchie, Jonathan M.
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CANNABINOIDS , *PARKINSON'S disease , *MOVEMENT disorders , *TARDIVE dyskinesia , *MARMOSETS - Abstract
Presents a study which assessed in nonhuman primates the role of endocannabinoid stimulation of cannabinoid CB1 receptors in the generation of symptoms of parkinsonism and L-DOPA-induced dyskinesia (LID). Effects of attenuating CB1 transmission with the selective CB1 antagonist rimonabant on parkinsonism and LID in the MPTP-lesioned marmoset; Symptoms of parkinsonism; Major complication of treatments for parkinsonism.
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- 2005
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187. Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells.
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Saliba, Soraya Wilke, Jauch, Hannah, Gargouri, Brahim, Keil, Albrecht, Hurrle, Thomas, Volz, Nicole, Mohr, Florian, van der Stelt, Mario, Bräse, Stefan, and Fiebich, Bernd L.
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INFLAMMATION ,ALZHEIMER'S disease ,NEURODEGENERATION ,MICROGLIA ,CENTRAL nervous system - Abstract
Background: Neuroinflammation plays a vital role in Alzheimer's disease and other neurodegenerative conditions. Microglia are the resident mononuclear immune cells of the central nervous system, and they play essential roles in the maintenance of homeostasis and responses to neuroinflammation. The orphan G-protein-coupled receptor 55 (GPR55) has been reported to modulate inflammation and is expressed in immune cells such as monocytes and microglia. However, its effects on neuroinflammation, mainly on the production of members of the arachidonic acid pathway in activated microglia, have not been elucidated in detail.Methods: In this present study, a series of coumarin derivatives, that exhibit GPR55 antagonism properties, were designed. The effects of these compounds on members of the arachidonic acid cascade were studied in lipopolysaccharide (LPS)-treated primary rat microglia using Western blot, qPCR, and ELISA.Results: We demonstrate here that the various compounds with GPR55 antagonistic activities significantly inhibited the release of PGE2 in primary microglia. The inhibition of LPS-induced PGE2 release by the most potent candidate KIT 17 was partially dependent on reduced protein synthesis of mPGES-1 and COX-2. KIT 17 did not affect any key enzyme involved on the endocannabinoid system. We furthermore show that microglia expressed GPR55 and that a synthetic antagonist of the GPR receptor (ML193) demonstrated the same effect of the KIT 17 on the inhibition of PGE2.Conclusions: Our results suggest that KIT 17 is acting as an inverse agonist on GPR55 independent of the endocannabinoid system. Targeting GPR55 might be a new therapeutic option to treat neurodegenerative diseases with a neuroinflammatory background such as Alzheimer's disease, Parkinson, and multiple sclerosis (MS). [ABSTRACT FROM AUTHOR]- Published
- 2018
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188. Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells
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Soethoudt, Marjolein, Stolze, Sara C., Westphal, Matthias V., Van Stralen, Luuk, Martella, Andrea, Van Rooden, Eva J., Guba, Wolfgang, Varga, Zoltan V., Deng, Hui, Van Kasteren, Sander I., Grether, Uwe, IJzerman, Adriaan P., Pacher, Pal, Carreira, Erick M., Overkleeft, Herman S., Ioan-Facsinay, Andreea, Heitman, Laura H., and Van der Stelt, Mario
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3. Good health - Abstract
Journal of the American Chemical Society, 140 (19), ISSN:0002-7863, ISSN:1520-5126
189. Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity
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Stuart, Jordyn, Lichtman, Aron H, Gens, Marianela Dalghi, Chicca, Andrea, Van Der Stelt, Mario, MacDonald, Christa, Mastrangelo, Nicolina, Mock, Elliot D, Fingerle, Jürgen, Di Marzo, Vincenzo, Finlay, David, Deng, Hui, Grether, Uwe, De Petrocellis, Luciano, Heitman, Laura H, Fezza, Filomena, Grim, Travis W, Alachouzos, Georgios, Maccarrone, Mauro, De Vries, Henk, Xia, Lizi, Van Gils, Noortje, Pacher, Pal, Connor, Mark, Martella, Andrea, Baggelaar, Marc P, Soethoudt, Marjolein, Glass, Michelle, Gertsch, Jürg, Rothenhäusler, Benno, Ullmer, Christoph, and Perret, Camille
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570 Life sciences ,biology ,610 Medicine & health ,3. Good health - Abstract
The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.
190. Disruption of tonic endocannabinoid signalling triggers cellular, behavioural and neuroendocrine responses consistent with a stress response.
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Petrie, Gavin N., Balsevich, Georgia, Füzesi, Tamás, Aukema, Robert J., Driever, Wouter P. F., van der Stelt, Mario, Bains, Jaideep S., and Hill, Matthew N.
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CORTICOTROPIN releasing hormone , *HYPOTHALAMUS , *CELL communication , *HYPOTHALAMIC-pituitary-adrenal axis , *PARAVENTRICULAR nucleus - Abstract
Background and Purpose: Endocannabinoid (eCB) signalling gates many aspects of the stress response, including the hypothalamic--pituitary--adrenal (HPA) axis. The HPA axis is controlled by corticotropin releasing hormone (CRH) producing neurons in the paraventricular nucleus of the hypothalamus (PVN). Disruption of eCB signalling increases drive to the HPA axis, but the mechanisms subserving this process are poorly understood. Experimental Approach: Using an array of cellular, endocrine and behavioural readouts associated with activation of CRH neurons in the PVN, we evaluated the contributions of tonic eCB signalling to the generation of a stress response. Key Results: The CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243 and NAPE PLD inhibitor LEI401 all uniformly increased Fos in the PVN, unmasked stress-linked behaviours, such as grooming, and increased circulating CORT, recapitulating the effects of stress. Similar effects were also seen after direct administration of AM251 into the PVN, while optogenetic inhibition of PVN CRH neurons ameliorated stress-like behavioural changes produced by disruption of eCB signalling. Conclusions and Implications: These data indicate that under resting conditions, constitutive eCB signalling restricts activation of the HPA axis through local regulation of CRH neurons in the PVN. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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191. Structure-Based Design of β5c Selective Inhibitors of Human Constitutive Proteasomes.
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Bo-Tao Xin, de Bruin, Gerjan, Huber, Eva M., Besse, Andrej, Florea, Bogdan I., Filippov, Dmitri V., van der Marel, Gijsbert A., Kisselev, Alexei F., van der Stelt, Mario, Driessen, Christoph, Groll, Michael, and Overkleeft, Herman S.
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- 2016
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192. Anandamide and other N-acylethanolamines: A class of signaling lipids with therapeutic opportunities.
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Mock, Elliot D., Gagestein, Berend, and van der Stelt, Mario
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CANNABINOID receptors , *ANANDAMIDE , *G protein coupled receptors , *LIPIDS , *ION channels , *NEUROBEHAVIORAL disorders - Abstract
N -acylethanolamines (NAEs), including N -palmitoylethanolamine (PEA), N -oleoylethanolamine (OEA), N -arachidonoylethanolamine (AEA, anandamide), N -docosahexaenoylethanolamine (DHEA, synaptamide) and their oxygenated metabolites are a lipid messenger family with numerous functions in health and disease, including inflammation, anxiety and energy metabolism. The NAEs exert their signaling role through activation of various G protein-coupled receptors (cannabinoid CB 1 and CB 2 receptors, GPR55, GPR110, GPR119), ion channels (TRPV1) and nuclear receptors (PPAR-α and PPAR-γ) in the brain and periphery. The biological role of the oxygenated NAEs, such as prostamides, hydroxylated anandamide and DHEA derivatives, are less studied. Evidence is accumulating that NAEs and their oxidative metabolites may be aberrantly regulated or are associated with disease severity in obesity, metabolic syndrome, cancer, neuroinflammation and liver cirrhosis. Here, we comprehensively review NAE biosynthesis and degradation, their metabolism by lipoxygenases, cyclooxygenases and cytochrome P450s and the biological functions of these signaling lipids. We discuss the latest findings and therapeutic potential of modulating endogenous NAE levels by inhibition of their degradation, which is currently under clinical evaluation for neuropsychiatric disorders. We also highlight NAE biosynthesis inhibition as an emerging topic with therapeutic opportunities in endocannabinoid and NAE signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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193. 2-AG-Mediated Control of GABAergic Signaling Is Impaired in a Model of Epilepsy.
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Colangeli, Roberto, Morena, Maria, Werner, Allison, Thompson, Roger J., van der Stelt, Mario, Pittman, Quentin J., Hill, Matthew N., and Teskey, G. Campbell
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MUSCARINIC acetylcholine receptors , *LONG-term synaptic depression , *EPILEPSY , *NEUROPLASTICITY , *NEURAL transmission , *GABA - Abstract
Repeated seizures result in a persistent maladaptation of endocannabinoid (eCB) signaling, mediated part by anandamide signaling deficiency in the basolateral amygdala (BLA) that manifests as aberrant synaptic function and altered emotional behavior. Here, we determined the effect of repeated seizures (kindling) on 2-arachidonoylglycerol (2-AG) signaling on GABA transmission by directly measuring tonic and phasic eCB-mediated retrograde signaling in an in vitro BLA slice preparation from male rats. We report that both activity-dependent and muscarinic acetylcholine receptor (mAChR)-mediated depression of GABA synaptic transmission was reduced following repeated seizure activity. These effects were recapitulated in sham rats by preincubating slices with the 2-AG synthesizing enzyme inhibitor DO34. Conversely, preincubating slices with the 2-AG degrading enzyme inhibitor KML29 rescued activity-dependent 2-AG signaling, but not mAChR-mediated synaptic depression, over GABA transmission in kindled rats. These effects were not attributable to a change in cannabinoid type 1 (CB1) receptor sensitivity or altered 2-AG tonic signaling since the application of the highly selective CB1 receptor agonist CP55,940 provoked a similar reduction in GABA synaptic activity in both sham and kindled rats, while no effect of either DO34 or of the CB1 inverse agonist AM251 was observed on frequency and amplitude of spontaneous IPSCs in either sham or kindled rats. Collectively, these data provide evidence that repeated amygdala seizures persistently alter phasic 2-AG-mediated retrograde signaling at BLA GABAergic synapses, probably by impairing stimulus-dependent 2-AG synthesis/release, which contributes to the enduring aberrant synaptic plasticity associated with seizure activity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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194. Forebrain-Specific Inactivation of Gq/G11 Family G Proteins Results in Age-Dependent Epilepsy and Impaired Endocannabinoid Formation.
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Wettschureck, Nina, Van der Stelt, Mario, Tsubokawa, Hiroshi, Krestel, Heinz, Moers, Alexandra, Petrosino, Stefania, Schütz, Günther, Di Marzo, Vincenzo, and Offermanns, Stefan
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LECTINS , *G proteins , *NERVOUS system , *MICE , *NEURONS - Abstract
Metabotropic receptors coupled to Gq/G11 family G proteins critically contribute to nervous system functions by modulating synaptic transmission, often facilitating excitation. We investigated the role of Gq/G11 family G proteins in the regulation of neuronal excitability in mice that selectively lack the α-subunits of Gq and G11, Gαq and Gα11, respectively, in forebrain principal neurons. Surprisingly, mutant mice exhibited increased seizure susceptibility, and the activation of neuroprotective mechanisms was impaired. We found that endocannabinoid levels were reduced under both basal and excitotoxic conditions and that increased susceptibility to kainic acid could be normalized by the enhancement of endocannabinoid levels with an endocannabinoid reuptake inhibitor, while the competitive cannabinoid type 1 receptor antagonist SR141716A did not cause further aggravation. These findings indicate that Gq/G11 family G proteins negatively regulate neuronal excitability in vivo and suggest that impaired endocannabinoid formation in the absence of Gq/G11 contributes to this phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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195. Live‐Cell Imaging of Sterculic Acid—a Naturally Occurring 1,2‐Cyclopropene Fatty Acid—by Bioorthogonal Reaction with Turn‐On Tetrazine‐Fluorophore Conjugates.
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Bertheussen, Kristine, van de Plassche, Merel, Bakkum, Thomas, Gagestein, Berend, Ttofi, Iakovia, Sarris, Alexi J. C., Overkleeft, Herman S., van der Stelt, Mario, and van Kasteren, Sander I.
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FATTY acids , *UNSATURATED fatty acids , *LIGATION reactions , *DIELS-Alder reaction , *OLEIC acid - Abstract
In the field of lipid research, bioorthogonal chemistry has made the study of lipid uptake and processing in living systems possible, whilst minimising biological properties arising from detectable pendant groups. To allow the study of unsaturated free fatty acids in live cells, we here report the use of sterculic acid, a 1,2‐cyclopropene‐containing oleic acid analogue, as a bioorthogonal probe. We show that this lipid can be readily taken up by dendritic cells without toxic side effects, and that it can subsequently be visualised using an inverse electron‐demand Diels–Alder reaction with quenched tetrazine‐fluorophore conjugates. In addition, the lipid can be used to identify changes in protein oleoylation after immune cell activation. Finally, this reaction can be integrated into a multiplexed bioorthogonal reaction workflow by combining it with two sequential copper‐catalysed Huisgen ligation reactions. This allows for the study of multiple biomolecules in the cell simultaneously by multimodal confocal imaging. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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196. Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala.
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Yasmin, Farhana, Colangeli, Roberto, Morena, Maria, Filipski, Sarah, van der Stelt, Mario, Pittman, Quentin J., Hillard, Cecilia J., Teskey, G. Campbell, McEwen, Bruce S., Hill, Matthew N., and Chattarji, Sumantra
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CANNABINOID receptors , *IMMOBILIZATION stress , *AMYGDALOID body , *FATTY acids , *MENTAL illness - Abstract
Even a brief exposure to severe stress strengthens synaptic connectivity days later in the amygdala, a brain area implicated in the affective symptoms of stress-related psychiatric disorders. However, little is known about the synaptic signaling mechanisms during stress that eventually culminate in its delayed impact on the amygdala. Hence, we investigated early stress-induced changes in amygdalar synaptic signaling in order to prevent its delayed effects. Whole-cell recordings in basolateral amygdala (BLA) slices from rats revealed higher frequency of miniature excitatory postsynaptic currents (mEPSCs) immediately after 2-h immobilization stress. This was replicated by inhibition of cannabinoid receptors (CB1R), suggesting a role for endocannabinoid (eCB) signaling. Stress also reduced N-arachidonoylethanolamine (AEA), an endogenous ligand of CB1R. Since stress-induced activation of fatty acid amide hydrolase (FAAH) reduces AEA, we confirmed that oral administration of an FAAH inhibitor during stress prevents the increase in synaptic excitation in the BLA soon after stress. Although stress also caused an immediate reduction in synaptic inhibition, this was not prevented by FAAH inhibition. Strikingly, FAAH inhibition during the traumatic stressor was also effective 10 d later on the delayed manifestation of synaptic strengthening in BLA neurons, preventing both enhanced mEPSC frequency and increased dendritic spine-density. Thus, oral administration of an FAAH inhibitor during a brief stress prevents the early synaptic changes that eventually build up to hyperexcitability in the amygdala. This framework is of therapeutic relevance because of growing interest in targeting eCB signaling to prevent the gradual development of emotional symptoms and underlying amygdalar dysfunction triggered by traumatic stress. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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197. Dual allosteric and orthosteric pharmacology of synthetic analog cannabidiol-dimethylheptyl, but not cannabidiol, on the cannabinoid CB2 receptor.
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Bouma, Jara, Broekhuis, Jeremy D., van der Horst, Cas, Kumar, Poulami, Ligresti, Alessia, van der Stelt, Mario, and Heitman, Laura H.
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CANNABIS (Genus) , *CANNABINOID receptors , *CANNABIDIOL , *G proteins , *MOLECULAR pharmacology , *BINDING sites , *PHARMACOLOGY , *G protein coupled receptors - Abstract
[Display omitted] Cannabinoid CB 2 receptor (CB 2 R) is a class A G protein-coupled receptor (GPCR) involved in a broad spectrum of physiological processes and pathological conditions. For that reason, targeting CB 2 R might provide therapeutic opportunities in neurodegenerative disorders, neuropathic pain, inflammatory diseases, and cancer. The main components from Cannabis sativa , such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), have been therapeutically exploited and synthetically-derived analogs have been generated. One example is cannabidiol-dimethylheptyl (CBD-DMH), which exhibits anti-inflammatory effects. Nevertheless, its pharmacological mechanism of action is not yet fully understood and is hypothesized for multiple targets, including CB 2 R. The aim of this study was to further investigate the molecular pharmacology of CBD-DMH on CB 2 R while CBD was taken along as control. These compounds were screened in equilibrium and kinetic radioligand binding studies and various functional assays, including G protein activation, inhibition of cAMP production and ß-arrestin-2 recruitment. In dissociation studies, CBD-DMH allosterically modulated the radioligand binding. Furthermore, CBD-DMH negatively modulated the G protein activation of reference agonists CP55,940, AEA and 2-AG, but not the agonist-induced ß-arrestin-2 recruitment. Nevertheless, CBD-DMH also displayed competitive binding to CB 2 R and partial agonism on G protein activation, inhibition of cAMP production and ß-arrestin-2 recruitment. CBD did not exhibit such allosteric behavior and only very weakly bound CB 2 R without activation. This study shows a dual binding mode of CBD-DMH, but not CBD, to CB 2 R with the suggestion of two different binding sites. Altogether, it encourages further research into this dual mechanism which might provide a new class of molecules targeting CB 2 R. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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198. Improving CLL Vγ9Vδ2-T--cell fitness for cellular therapy by ex vivo activation and ibrutinib.
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de Weerdt, Iris, Hofland, Tom, Lameris, Roeland, Endstra, Sanne, Jongejan, Aldo, Moerland, Perry D., de Bruin, Renee C. G., Remmerswaal, Ester B. M., ten Berge, Ineke J. M., Liu, Nora, van der Stelt, Mario, Faber, Laura M., Levin, Mark-David, Eldering, Eric, Tonino, Sanne H., de Gruijl, Tanja D., van der Vliet, Hans J., and Kater, Arnon P.
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CHRONIC lymphocytic leukemia treatment , *T cells , *MAJOR histocompatibility complex , *CYTOKINES , *B cells - Abstract
The efficacy of autologous (αβ) T-cell--based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex--independent mechanism. We studied whether Vγ9Vδ2 cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2 cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2 cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2 cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2--cell function in CLL patients. Dysfunction of Vγ9Vδ2 cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2 cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2 cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2 cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2 cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2 cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-cell--based therapy with ibrutinib. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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199. Evaluation of different drug classes on transient sciatic nerve injury-depressed marble burying in mice.
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Wilkerson, Jenny L., Curry, Zachary A., Kinlow, Pamela D., Mason, Brittany L., Ku-Lung Hsu, van der Stelt, Mario, Cravatt, Benjamin F., Lichtman, Aron H., and Hsu, Ku-Lung
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CANNABINOIDS , *CHRONIC pain treatment , *HYPERALGESIA treatment , *DIAZEPAM , *VALDECOXIB , *THERAPEUTICS , *ANTIDEPRESSANTS , *ANALGESICS , *ANIMAL behavior , *ANIMALS , *BEHAVIOR , *BIOLOGICAL models , *MENTAL depression , *HYPERALGESIA , *MICE , *RESEARCH funding , *SCIATICA , *PAIN measurement , *DISEASE complications - Abstract
A great need exists for the identification of new effective analgesics to treat sustained pain. However, most preclinical nociceptive assays measure behavioral responses evoked by noxious stimuli (ie, pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury (CCI) of the sciatic nerve elicits common pain-stimulated responses (ie, mechanical allodynia and thermal hyperalgesia) as well as reduces marble burying/digging behaviors that occur during the early stages of the neuropathy and resolve within 1 week. Although drugs representing distinct classes of analgesics (ie, morphine, valdecoxib, and gabapentin) reversed both CCI-induced and CCI-depressed nociceptive measures, diazepam lacked antinociceptive effects in all assays and the kappa-opioid receptor agonist U69593 reversed pain-stimulated, but not pain-depressed behaviors. In addition, we tested drugs targeting distinct components of the endocannabinoid system, including agonists at cannabinoid receptors type 1 (CB1) and type 2 (CB2), as well as inhibitors of the endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase. Each of these drugs reversed all CCI-induced nociceptive measures, with the exception of the fatty acid amide hydrolase inhibitor that reversed pain-stimulated behaviors, only. These findings support the use of the mouse marble-burying assay as a model of pain-depressed behavior within the first week of sciatic nerve injury to examine candidate analgesics. These data also support existing preclinical research that cannabinoid receptor agonists and inhibitors of endocannabinoid-regulating enzymes merit consideration for the treatment of pain. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
200. Structure-kinetic relationship studies of cannabinoid CB2 receptor agonists reveal substituent-specific lipophilic effects on residence time.
- Author
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Soethoudt, Marjolein, Hoorens, Mark W.h., Doelman, Ward, Martella, Andrea, Van Der Stelt, Mario, and Heitman, Laura H.
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CANNABINOID receptors , *CHEMICAL agonists , *LIGANDS (Biochemistry) , *PROTEIN binding , *LEAD compounds , *BIOGEOCHEMICAL residence time - Abstract
A decade ago, the drug-target residence time model has been (re-)introduced, which describes the importance of binding kinetics of ligands on their protein targets. Since then, it has been applied successfully for multiple protein targets, including GPCRs, for the development of lead compounds with slow dissociation kinetics (i.e. long target residence time) to increase in vivo efficacy or with short residence time to prevent on-target associated side effects. To date, this model has not been applied in the design and pharmacological evaluation of novel selective ligands for the cannabinoid CB 2 receptor (CB 2 R), a GPCR with therapeutic potential in the treatment of tissue injury and inflammatory diseases. Here, we have investigated the relationships between physicochemical properties, binding kinetics and functional activity in two different signal transduction pathways, G protein activation and β-arrestin recruitment. We synthesized 24 analogues of 3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazoleidine-2,4-dione (LEI101), our previously reported in vivo active and CB 2 R-selective agonist, with varying basicity and lipophilicity. We identified a positive correlation between target residence time and functional potency due to an increase in lipophilicity on the alkyl substituents, which was not the case for the amine substituents. Basicity of the agonists did not show a relationship with affinity, residence time or functional activity. Our findings provide important insights about the effects of physicochemical properties of the specific substituents of this scaffold on the binding kinetics of agonists and their CB 2 R pharmacology. This work therefore shows how CB 2 R agonists can be designed to have optimal kinetic profiles, which could aid the lead optimization process in drug discovery for the study or treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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