16292-90-3Relevant academic research and scientific papers
Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain
Brindisi, Margherita,Borrelli, Giuseppe,Brogi, Simone,Grillo, Alessandro,Maramai, Samuele,Paolino, Marco,Benedusi, Mascia,Pecorelli, Alessandra,Valacchi, Giuseppe,Di Cesare Mannelli, Lorenzo,Ghelardini, Carla,Allarà, Marco,Ligresti, Alessia,Minetti, Patrizia,Campiani, Giuseppe,di Marzo, Vincenzo,Butini, Stefania,Gemma, Sandra
, p. 2090 - 2103 (2018/09/11)
The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB1R), were selected for further studies. Results of cell-based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h, 5 i, and our reference compound 3 ([3-(3-carbamoylpyrrol-1-yl)phenyl] N-(5-phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox-sensitive transcription factor NF-κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10 mg kg?1 all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.
A probable hydrogen-bonded meisenheimer complex: An unusually high S NAr reactivity of nitroaniline derivatives with hydroxide ion in aqueous media
Imoto, Mitsutaka,Matsui, Yasunori,Takeda, Motonori,Tamaki, Akihiro,Taniguchi, Hisaji,Mizuno, Kazuhiko,Ikeda, Hiroshi
experimental part, p. 6356 - 6361 (2011/10/05)
Observations show that nitroanilines exhibit an unusually high S NAr reactivity with OH- in aqueous media in reactions that produce nitrophenols. SNAr reaction of 4-nitroaniline (2a) in aqueous NaOH for 16 h yields 4-nitrophenol (4a) quantitatively, whereas a similar reaction of 4-nitrochlorobenzene (1a) gave 4a in 2% yield together with recovered 1a in 97%, suggesting that the leaving ability of the NH2 group far surpasses that of Cl under these conditions. An essential feature of SNAr reactions of nitroanilines is probably that the NH2 leaving group participates in a hydrogen-bonding interaction with H 2O. Density functional theory (DFT) calculations for a set of 4-nitroaniline, OH-, and H2O suggest a possible formation of a Meisenheimer complex stabilized by hydrogen-bonding interactions and a six-membered ring structure. The results obtained here contrast with conventional SNAr reactivity profiles in which nitroanilines are nearly unreactive with nucleophiles in organic solvents.
