The Experts below are selected from a list of 930 Experts worldwide ranked by ideXlab platform
Michael Kassiou - One of the best experts on this subject based on the ideXlab platform.
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pharmacology of cumyl carboxamide synthetic cannabinoid new psychoactive substances nps cumyl bica cumyl pica cumyl 5f pica cumyl 5f pinaca and their analogues
ACS Chemical Neuroscience, 2017Co-Authors: Mitchell Longworth, Richard C Kevin, Rochelle Boyd, Mark Connor, Iain S Mcgregor, Michael KassiouAbstract:Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and Indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues. All cumyl-derived SCs were potent, efficacious agonists at CB1 (EC50 = 0.43–12.3 nM) and CB2 (EC50 = 11.3–122 nM) receptors in a fluorometric assay of membrane potential, with selectivity for CB1 activation (3.1–53 times over CB2). CUMYL-PICA and CUMYL-5F-PICA were evaluated in rats using biotelemetry, and induced hypothermia and bradycardia at doses of 1 mg/kg. Hypothermia was reversed by pretreatment with a CB1, but not CB2, ...
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Pharmacology of Cumyl-Carboxamide Synthetic Cannabinoid New Psychoactive Substances (NPS) CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-5F-PINACA, and Their Analogues
2017Co-Authors: Mitchell Longworth, Richard C Kevin, Rochelle Boyd, Mark Connor, Iain S Mcgregor, Samuel D. Banister, Michael KassiouAbstract:Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and Indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues. All cumyl-derived SCs were potent, efficacious agonists at CB1 (EC50 = 0.43–12.3 nM) and CB2 (EC50 = 11.3–122 nM) receptors in a fluorometric assay of membrane potential, with selectivity for CB1 activation (3.1–53 times over CB2). CUMYL-PICA and CUMYL-5F-PICA were evaluated in rats using biotelemetry, and induced hypothermia and bradycardia at doses of 1 mg/kg. Hypothermia was reversed by pretreatment with a CB1, but not CB2, antagonist, confirming that cumyl-derived SCs are cannabimimetic in vivo
Megan K Macala - One of the best experts on this subject based on the ideXlab platform.
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discovery of a 3 4 pyrimidinyl indazole mli 2 an orally available and selective leucine rich repeat kinase 2 lrrk2 inhibitor that reduces brain kinase activity
Journal of Medicinal Chemistry, 2017Co-Authors: Jack D Scott, Duane E Demong, Thomas J Greshock, Kallol Basu, Xing Dai, Joel M Harris, Alan Hruza, Sueing Lin, Hong Liu, Megan K MacalaAbstract:Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson’s disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these Indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
Mitchell Longworth - One of the best experts on this subject based on the ideXlab platform.
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pharmacology of cumyl carboxamide synthetic cannabinoid new psychoactive substances nps cumyl bica cumyl pica cumyl 5f pica cumyl 5f pinaca and their analogues
ACS Chemical Neuroscience, 2017Co-Authors: Mitchell Longworth, Richard C Kevin, Rochelle Boyd, Mark Connor, Iain S Mcgregor, Michael KassiouAbstract:Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and Indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues. All cumyl-derived SCs were potent, efficacious agonists at CB1 (EC50 = 0.43–12.3 nM) and CB2 (EC50 = 11.3–122 nM) receptors in a fluorometric assay of membrane potential, with selectivity for CB1 activation (3.1–53 times over CB2). CUMYL-PICA and CUMYL-5F-PICA were evaluated in rats using biotelemetry, and induced hypothermia and bradycardia at doses of 1 mg/kg. Hypothermia was reversed by pretreatment with a CB1, but not CB2, ...
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Pharmacology of Cumyl-Carboxamide Synthetic Cannabinoid New Psychoactive Substances (NPS) CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-5F-PINACA, and Their Analogues
2017Co-Authors: Mitchell Longworth, Richard C Kevin, Rochelle Boyd, Mark Connor, Iain S Mcgregor, Samuel D. Banister, Michael KassiouAbstract:Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and Indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues. All cumyl-derived SCs were potent, efficacious agonists at CB1 (EC50 = 0.43–12.3 nM) and CB2 (EC50 = 11.3–122 nM) receptors in a fluorometric assay of membrane potential, with selectivity for CB1 activation (3.1–53 times over CB2). CUMYL-PICA and CUMYL-5F-PICA were evaluated in rats using biotelemetry, and induced hypothermia and bradycardia at doses of 1 mg/kg. Hypothermia was reversed by pretreatment with a CB1, but not CB2, antagonist, confirming that cumyl-derived SCs are cannabimimetic in vivo
Ibon Alkorta - One of the best experts on this subject based on the ideXlab platform.
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supramolecular organization of perfluorinated 1h Indazoles in the solid state using x ray crystallography ssnmr and sensitive vcd and non sensitive mir fir and raman to chirality vibrational spectroscopies
Physical Chemistry Chemical Physics, 2017Co-Authors: Maria Mar Quesadamoreno, Juan Ramon Avilesmoreno, Juan Jesus Lopezgonzalez, Kane Jacob, Laure Vendier, Michel Etienne, Ibon AlkortaAbstract:1H-Indazole derivatives exhibit a remarkable property since some of them form chiral supramolecular structures starting from achiral monomers. The present work deals with the study of three perfluorinated 1H-Indazoles that resolve spontaneously as conglomerates. These conglomerates can contain either a pure enantiomer (one helix) or a mixture of both enantiomers (both helices) with an enantiomeric excess (e.e.) of one of them. The difficulty of the structural analysis of these types of compounds is thus clear. We outline a complete strategy to determine the structures and configurations (M or P helices) of the enantiomers (helices) forming the conglomerates of these perfluorinated 1H-Indazoles based on X-ray crystallography, solid state NMR spectroscopy and different solid state vibrational spectroscopies that are either sensitive (VCD) or not (FarIR, IR and Raman) to chirality, together with quantum chemical calculations (DFT).
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the reaction of nh Indazoles with 1 fluoro 2 4 dinitrobenzene the unusual formation of benzotriazole n oxides
New Journal of Chemistry, 2013Co-Authors: Ibon Alkorta, Jose Elguero, Fernando P Cossio, Nieves Fresno, Laura Hernandezfolgado, Santiago Garciagranda, Laura Menendeztaboada, Ruth Perezfernandez, Felipe Reviriego, Lucia VazquezvinuelaAbstract:When N-unsubstituted Indazoles, like indazole itself, reacted with 1-fluoro-2,4-dinitrobenzene or 1-chloro-2,4,6-trinitrobenzene, three products were obtained whose structures were determined by X-ray diffraction. Besides the two N-substituted nitroaryl derivatives, a third compound was obtained with the same molecular formula (C13H8N4O4) to which was assigned the structure of a derivative of benzotriazole N-oxide. With the combined use of crystallography, NMR and DFT calculations this reaction was studied with special stress on the mechanism of formation of the benzotriazole-N-oxide.
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the chiral structure of 1h Indazoles in the solid state a crystallographic vibrational circular dichroism and computational study
New Journal of Chemistry, 2012Co-Authors: Juan Jesus Lopez Gonzalez, Francisco Partal Urena, Juan Ramon Aviles Moreno, Ignasi Mata, Elies Molins, Rosa M Claramunt, Concepcion Lopez, Ibon Alkorta, Jose ElgueroAbstract:A survey of the Cambridge Crystallographic Database reveals that there are 17 1H-Indazoles forming dimers (7), trimers (4) and catemers or chains (6). Amongst the catemers there is one centrosymmetric compound and five non-centrosymmetric ones that crystallize in chiral helices, either M or P, including indazole itself, whose structure has been determined anew. An explanation will be provided for how an achiral molecule crystallizes in a chiral space group. The second part of the paper is devoted to the use of Vibrational Circular Dichroism (VCD) for determining the absolute configuration of a crystal of indazole. This previously needs the complete assignment of its IR and Raman spectra in solution and in the solid-state based on B3LYP/6-31G(d) calculations of indazole dimers and trimers, which are already chiral.
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Synthesis and biological evaluation of indazole derivatives
European journal of medicinal chemistry, 2011Co-Authors: Rosa M Claramunt, Concepcion Lopez, Ibon Alkorta, Jose Elguero, Ana López, Carlos Pérez-medina, Marta Pérez-torralba, Germaine Escames, Darío Acuña-castroviejoAbstract:The inhibition of neuronal and inducible nitric oxide synthases (nNOS and iNOS) by a series of 36 Indazoles has been evaluated, showing that most of the assayed derivatives are better iNOS than nNOS inhibitors. A parabolic model relating the iNOS inhibition percentage with the difference, Erel, between stacking and apical interaction energies of Indazoles with the active site of the NOS enzyme has been established.
Jack D Scott - One of the best experts on this subject based on the ideXlab platform.
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discovery of a 3 4 pyrimidinyl indazole mli 2 an orally available and selective leucine rich repeat kinase 2 lrrk2 inhibitor that reduces brain kinase activity
Journal of Medicinal Chemistry, 2017Co-Authors: Jack D Scott, Duane E Demong, Thomas J Greshock, Kallol Basu, Xing Dai, Joel M Harris, Alan Hruza, Sueing Lin, Hong Liu, Megan K MacalaAbstract:Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson’s disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these Indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
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Discovery of a 3‑(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
2017Co-Authors: Jack D Scott, Duane E Demong, Thomas J Greshock, Kallol Basu, Xing Dai, Alan Hruza, Sueing Lin, Joel Harris, Hong LiuAbstract:Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson’s disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these Indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2
