57303-04-5Relevant academic research and scientific papers
S-Arachidonoyl-2-thioglycerol synthesis and use for fluorimetric and colorimetric assays of monoacylglycerol lipase
Casida, John E.,Gulevich, Alexander G.,Sarpong, Richmond,Bunnelle, Eric M.
, p. 1942 - 1947 (2010)
We report the first synthesis of 2-thioglycerol and S-arachidonoyl-2-thioglycerol (the thioester analog of the endocannabinoid 2-arachidonoylglycerol) in an eight or nine step procedure with a yield of ～25% and establish the use of this substrate for maleimide-based fluorescent and dithiobis(2-nitrobenzoic acid)-based colorimetric assays of human recombinant monoacylglycerol (MAG) lipase (hMAGL) and human brain membrane MAG hydrolase activity. Inhibitor structure-activity relationships observed here for hMAGL and 2-ATG correlate well (r2 = 0.93, n = 9) with earlier findings for mouse brain MAG hydrolase with non-thiol substrates.
Oxygenated metabolites of anandamide and 2-arachidonoylglycerol: Conformational analysis and interaction with cannabinoid receptors, membrane transporter, and fatty acid amide hydrolase
Van der Stelt, Mario,Van Kuik, J. Albert,Bari, Monica,Van Zadelhoff, Guus,Leeflang, Bas R.,Veldink, Gerrit A.,Finazzi-Agrò, Alessandro,Vliegenthart, Johannes F. G.,Maccarrone, Mauro
, p. 3709 - 3720 (2002)
This study was aimed at finding structural requirements for the interaction of the acyl chain of endocannabinoids with cannabinoid receptors, membrane transporter protein, and fatty acid amide hydrolase (FAAH). To this end, the flexibility of the acyl chain was restricted by introduction of an 1-hydroxy-2Z,4E-pentadiene system in anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) at various positions using different lipoxygenases. This brought about selectivity and attenuated the binding potency of AEA and 2-AG. Although the displacement constants were modest, 15(S)-hydroxy-eicosa-5Z,8Z,11Z,-13E-tetraenoyl-N-(2-hydroxyethyl)amine was found to bind selectively to the CB1 receptor, whereas its 1-arachidonoyl-sn-glycerol analogue and 13(S)-hydroxy-octadeca-9Z,11E-dienoyl-N-(2-hydroxyethyl)amine could selectively bind to the CB2 receptor. 11(S)-Hydroxy-eicosa-5Z,8Z,12E,14Z-tetraenoyl-N-(2-hydroxyethyl)amine did not bind to either receptor, whereas 12(S)-hydroxy-eicosa-5Z,8Z,10E,14Z -tetraenoyl-N-(2-hydroxyethyl)amine did bind to both CB receptors with an affinity similar to that of AEA. All oxygenated anandamide derivatives were good inhibitors of FAAH (low micromolar Ki) but were ineffective on the AEA transporter. 2-AG rapidly isomerizes into 1(3)-arachidonoyl-sn-glycerol. Both 1- and 3-arachidonoyl-sn-glycerol did not bind to either CB receptor and did not interfere with AEA transport. Thus, after it is isomerized, 2-AG is inactivated, thereby decreasing effective concentrations of 2-AG. Analysis of 1H NMR spectra revealed that chloroform did not induce notably different conformations in the acyl chain of 15(S)-hydroxy-eicosa-5Z,8Z, 11Z,13E-tetraenoic acid as compared with water. Molecular dynamics (MD) simulations of AEA and its analogues in the presence of explicit water molecules revealed that a tightly folded conformation of the acyl chain is not the only requirement for CB1 binding. Structural details of the C2-C15 loop, such as an sp2 carbon at position 11, are necessary for receptor binding. The MD simulations may suggest that the average orientations of the pentyl tail of AEA and 12(S)-hydroxy-eicosa-5Z,8Z,-10E,14Z-tetraenoyl-N-(2-hydroxyethyl)amine are different from that of the low-affinity, inactive ligands.
Ruthenium(II)-Catalyzed Enantioselective ?-Lactams Formation by Intramolecular C-H Amidation of 1,4,2-Dioxazol-5-Ones
Xing, Qi,Chan, Chun-Ming,Yeung, Yiu-Wai,Yu, Wing-Yiu
supporting information, (2019/03/11)
We report the Ru-Catalyzed enantioselective annulation of 1,4,2-Dioxazol-5-Ones to furnish ?-Lactams in up to 97% yield and 98% ee via intramolecular carbonylnitrene C-H insertion. By employing chiral diphenylethylene diamine (dpen) as ligands bearing electron-Withdrawing arylsulfonyl substituents, the reactions occur with remarkable chemo- A nd enantioselectivities; the competing Curtius-Type rearrangement was largely suppressed. Enantioselective nitrene insertion to allylic/propargylic C-H bonds was also achieved with remarkable tolerance to the Ca?C and Ca‰iC bonds.
Ruthenium(II)-Catalyzed Enantioselective γ-Lactams Formation by Intramolecular C-H Amidation of 1,4,2-Dioxazol-5-ones
Xing, Qi,Chan, Chun-Ming,Yeung, Yiu-Wai,Yu, Wing-Yiu
supporting information, p. 3849 - 3853 (2019/04/25)
We report the Ru-catalyzed enantioselective annulation of 1,4,2-dioxazol-5-ones to furnish γ-lactams in up to 97% yield and 98% ee via intramolecular carbonylnitrene C - H insertion. By employing chiral diphenylethylene diamine (dpen) as ligands bearing electron-withdrawing arylsulfonyl substituents, the reactions occur with remarkable chemo- and enantioselectivities; the competing Curtius-type rearrangement was largely suppressed. Enantioselective nitrene insertion to allylic/propargylic C - H bonds was also achieved with remarkable tolerance to the C=C and C=C bonds.
Set-up and validation of a high throughput screening method for human monoacylglycerol lipase (MAGL) based on a new red fluorescent probe
Miceli, Matteo,Casati, Silvana,Ottria, Roberta,Di Leo, Simone,Eberini, Ivano,Palazzolo, Luca,Parravicini, Chiara,Ciuffreda, Pierangela
, (2019/06/20)
Monoacylglycerol lipase (MAGL) is a serine hydrolase that has a key regulatory role in controlling the levels of 2-arachidonoylglycerol (2-AG), the main signaling molecule in the endocannabinoid system. Identification of selective modulators of MAGL enables both to provide new tools for investigating pathophysiological roles of 2-AG, and to discover new lead compounds for drug design. The development of sensitive and reliable methods is crucial to evaluate this modulatory activity. In the current study, we report readily synthesized long-wavelength putative fluorogenic substrates with different acylic side chains to find a new probe for MAGL activity. 7-Hydroxyresorufinyl octanoate proved to be the best substrate thanks to the highest rate of hydrolysis and the best Km and Vmax values. In addition, in silico evaluation of substrates interaction with the active site of MAGL confirms octanoate resorufine derivative as the molecule of choice. The well-known MAGL inhibitors URB602 and methyl arachidonylfluorophosphonate (MAFP) were used for the assay validation. The assay was highly reproducible with an overall average Z0 value of 0.86. The fast, sensitive and accurate method described in this study is suitable for low-cost high-throughput screening (HTS) of MAGL modulators and is a powerful new tool for studying MAGL activity.
Discovery of Hydrolysis-Resistant Isoindoline N -Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration
Lin, Hua,Long, Jonathan Z.,Roche, Alexander M.,Svensson, Katrin J.,Dou, Florence Y.,Chang, Mi Ra,Strutzenberg, Timothy,Ruiz, Claudia,Cameron, Michael D.,Novick, Scott J.,Berdan, Charles A.,Louie, Sharon M.,Nomura, Daniel K.,Spiegelman, Bruce M.,Griffin, Patrick R.,Kamenecka, Theodore M.
supporting information, p. 3224 - 3230 (2018/04/23)
N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogues. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells. A class of unnatural N-acyl amino acid analogues, characterized by isoindoline-1-carboxylate head groups (37), were resistant to enzymatic degradation by PM20D1 and maintained uncoupling bioactivity in cells and in mice.
A novel class of cationic and non-peptidic small molecules as hits for the development of antimicrobial agents
Jiménez, Aranza,García, Pablo,De La Puente, Sofia,Madrona, Andrés,Camarasa, María José,Pérez-Pérez, María-Jesús,Quintela, José-Carlos,García-del Portillo, Francisco,San-Félix, Ana
, (2018/07/10)
Cationic and non-peptide small molecules containing a total of six positive charges arranged on one side and a long aliphatic tail on the other have been synthesized and tested against Gram-positive and Gram-negative bacteria. The positive charges have be
ANALGESIC COMPOUNDS
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Paragraph 0302, (2018/12/13)
Disclosed herein are compounds of Formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It), methods of synthesizing compounds of Formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It), and methods of using compounds of Formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It) as an analgesic.
Effects of metabolites of the analgesic agent dipyrone (metamizol) on rostral ventromedial medulla cell activity in mice
Maione, Sabatino,Radanova, Lilyana,De Gregorio, Danilo,Luongo, Livio,De Petrocellis, Luciano,Di Marzo, Vincenzo,Imming, Peter
, p. 115 - 122 (2015/02/19)
The molecular mechanism of action of dipyrone, a widely used antipyretic and non-opioid analgesic drug, is still not fully understood. Actions upon peripheral inflamed tissues as well as the central nervous system, especially upon the PAG-RVM axis, have b
Synthesis and evaluation of fatty acid amides on the N-oleoylethanolamide-like activation of peroxisome proliferator activated receptor α
Takao, Koichi,Noguchi, Kaori,Hashimoto, Yosuke,Shirahata, Akira,Sugita, Yoshiaki
, p. 278 - 285 (2015/04/22)
A series of fatty acid amides were synthesized and their peroxisome proliferator-activated receptor α (PPAR-α) agonistic activities were evaluated in a normal rat liver cell line, clone 9. The mRNAs of the PPAR-α downstream genes, carnitine-palmitoyltransferase-1 and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) as PPAR-α agonistic activities. We prepared nine oleic acid amides. Their PPAR-α agonistic activities were, in decreasing order, N-oleoylhistamine (OLHA), N-oleoylglycine, Oleamide, N-oleoyltyramine, N-oleoylsertonin, and Olvanil. The highest activity was found with OLHA. We prepared and evaluated nine N-acylhistamines (N-acyl-HAs). Of these, OLHA, C16:0-HA, and C18:1Δ9-trans-HA showed similar activity. Activity due to the different chain length of the saturated fatty acid peaked at C16:0-HA. The PPAR-α antagonist, GW6471, inhibited the induction of the PPAR-α downstream genes by OLHA and N-oleoylethanolamide (OEA). These data suggest that N-acyl-HAs could be considered new PPAR-α agonists.
