FAAH-Catalyzed C–C Bond Cleavage of a New Multitarget Analgesic Drug
| Autor: | David F. Woodward, Marco Allarà, Fabiana Piscitelli, Francesca Guida, Angela Amoresano, Jenny W. Wang, Livio Luongo, Rosa Maria Vitale, Cristoforo Silvestri, Vincenzo Di Marzo, Anna Illiano, Alessia Ligresti, Jose L. Martos, Pietro Amodeo, Gennaro Marino, Robert W. Carling, Sabatino Maione |
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| Přispěvatelé: | Ligresti, A, Silvestri, Ciro, Vitale, Rm, Martos, Jl, Piscitelli, F, Wang, Jw, Allarà, M, Carling, Rw, Luongo, L, Guida, F, Illiano, A, Amoresano, A, Maione, S, Amodeo, P, Woodward, Df, Di Marzo, V, Marino, G., Ligresti, Alessia, Silvestri, Cristoforo, Vitale, Rosa Maria, Martos, Jose L, Piscitelli, Fabiana, Wang, Jenny W, Allarà, Marco, Carling, Robert W, Luongo, Livio, Guida, Francesca, Illiano, Anna, Amoresano, Angela, Maione, Sabatino, Amodeo, Pietro, Woodward, David F, Di Marzo, Vincenzo, Marino, Gennaro |
| Rok vydání: | 2018 |
| Předmět: |
Physiology
Stereochemistry Cognitive Neuroscience Biochemistry Catalysis Amidohydrolases Amidase Mice 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems 0302 clinical medicine Fatty acid amide hydrolase multitarget inhibitors Amide medicine Animals Moiety Bond cleavage 030304 developmental biology Oxazole Analgesics 0303 health sciences C−C bond cleavage Cell Biology General Medicine Anandamide Bridged Bicyclo Compounds Heterocyclic Carbon Rats Molecular Docking Simulation chemistry Mechanism of action Cinnamates C-C bond cleavage FAAH mechanism Neuralgia medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | ACS chemical neuroscience (2018). doi:10.1021/acschemneuro.8b00315 info:cnr-pdr/source/autori:Ligresti A.; Silvestri C.; Vitale R.M.; Martos J.L.; Piscitelli F.; Wang J.W.; Allara M.; Carling R.W.; Luongo L.; Guida F.; Illiano A.; Amoresano A.; Maione S.; Amodeo P.; Woodward D.F.; Di Marzo V.; Marino G./titolo:FAAH-Catalyzed C-C Bond Cleavage of a New Multitarget Analgesic Drug/doi:10.1021%2Facschemneuro.8b00315/rivista:ACS chemical neuroscience/anno:2018/pagina_da:/pagina_a:/intervallo_pagine:/volume |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.8b00315 |
| Popis: | The discovery of extended catalytic versatilities is of great importance in both the chemistry and biotechnology fields. Fatty acid amide hydrolase (FAAH) belongs to the amidase signature superfamily and is a major endocannabinoid inactivating enzyme using an atypical catalytic mechanism involving hydrolysis of amide and occasionally ester bonds. FAAH inhibitors are efficacious in experimental models of neuropathic pain, inflammation, and anxiety, among others. We report a new multitarget drug, AGN220653, containing a carboxyamide-4-oxazole moiety and endowed with efficacious analgesic and anti-inflammatory activities, which are partly due to its capability of achieving inhibition of FAAH, and subsequently increasing the tissue concentrations of the endocannabinoid anandamide. This inhibitor behaves as a noncompetitive, slowly reversible inhibitor. Autoradiography of purified FAAH incubated with AGN220653, opportunely radiolabeled, indicated covalent binding followed by fragmentation of the molecule. Molecular docking suggested a possible nucleophilic attack by FAAH-Ser241 on the carbonyl group of the carboxyamide-4-oxazole moiety, resulting in the cleavage of the C-C bond between the oxazole and the carboxyamide moieties, instead of either of the two available amide bonds. MRM-MS analyses only detected the Ser241-assisted formation of the carbamate intermediate, thus confirming the cleavage of the aforementioned C-C bond. Quantum mechanics calculations were fully consistent with this mechanism. The study exemplifies how FAAH structural features and mechanism of action may override the binding and reactivity propensities of substrates. This unpredicted mechanism could pave the way to the future development of a completely new class of amidase inhibitors, of potential use against pain, inflammation, and mood disorders. |
| Databáze: | OpenAIRE |
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