Synthesis, Quantification, and Characterization of Fatty Acid Amides from In Vitro and In Vivo Sources

Fatty acid amides are a diverse family of underappreciated, biologically occurring lipids. Herein, the methods for the chemical synthesis and subsequent characterization of specific members of the fatty acid amide family are described. The synthetically prepared fatty acid amides and those obtained commercially are used as standards for the characterization and quantification of the fatty acid amides produced by biological systems, a fatty acid amidome. The fatty acid amidomes from mouse N18TG2 cells, sheep choroid plexus cells, Drosophila melanogaster, Bombyx mori, Apis mellifera, and Tribolium castaneum are presented.

Download Full-text

In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor

European Journal of Pharmacology ◽

10.1016/j.ejphar.2017.10.007 ◽

2017 ◽

Vol 815 ◽

pp. 42-48 ◽

Cited By ~ 9

Author(s):

Tomonari Watabiki ◽

Noriko Tsuji ◽

Tetsuo Kiso ◽

Tohru Ozawa ◽

Fumie Narazaki ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

Pharmacological Characterization ◽

Amide Hydrolase ◽

Fatty Acid Amide

Download Full-text

Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2013.04.077 ◽

2013 ◽

Vol 21 (14) ◽

pp. 4351-4357 ◽

Cited By ~ 26

Author(s):

Oleg Sadovski ◽

Justin W. Hicks ◽

Jun Parkes ◽

Roger Raymond ◽

José Nobrega ◽

...

Keyword(s):

Fatty Acid ◽

In Vivo Imaging ◽

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

Amide Hydrolase ◽

Fatty Acid Amide

Download Full-text

Assessment of NSAIDS as Potential Inhibitors of the Fatty Acid Amide Hydrolase I (FAAH-1) using Three Different Primary Fatty Acid Amide Substrates In Vitro

10.21203/rs.3.rs-728085/v1 ◽

2021 ◽

Author(s):

Julius T. Dongdem ◽

Gideon K. Helegbe ◽

Kwame Opare-Asamoah ◽

Cletus A. Wezena ◽

Augustine Ocloo

Keyword(s):

Fatty Acid ◽

Fatty Acid Amide Hydrolase ◽

Rank Order ◽

Acid Amide ◽

Substrate Affinity ◽

Cox Inhibitors ◽

Fatty Acid Amides ◽

Hydrolysis Of ◽

Fatty Acid Amide

Abstract Pain relief · remains a major subject of inadequately met need of patients. Therapeutic agents designed to treat pain and inflammation so far have low to moderate efficiencies with significant untoward side effects. FAAH-1 has been proposed as a promising target for the discovery of drugs to treat pain and inflammation without significant adverse effects. FAAH-1 is the primary enzyme accountable for the degradation of AEA and related fatty acid amides. Studies have revealed that the simultaneous inhibition of COX and FAAH-1 activities produce greater pharmacological efficiency with significantly lowered toxicity and ulcerogenic activity. Recently, the metabolism of endocannabinoids by COX-2 was suggested to be differentially regulated by NSAIDs. We analysed the affinity of ODA, ArDA and SyDA at the FAAH-1 in vitro and investigated the potency of selected NSAIDs on the hydrolysis of endocannabinoid-like molecules (ODA, ArDA and SyDA) by FAAH-1 from rat liver. NSAIDs were initially screened at 500 µM after which those that exhibited greater potency were further analysed over a range of inhibitor concentrations. The substrate affinity of FAAH-1 obtained, increased in a rank order of ODA < ArDA < SyDA with resultant Vmax values in a rank order of ArDA > ODA > SyDA. The selected NSAIDs caused a concentration-dependent inhibition of FAAH-1 activity with sulindac, carprofen and meclofenamate exhibiting the greatest potency. Michaelis-Menten analysis suggested the mode of inhibition of FAAH-1 hydrolysis of both ODA and ArDA by meclofenamate and indomethacin to be non-competitive in nature. Our data therefore suggest potential for study of these compounds as combined FAAH-1-COX inhibitors.

Download Full-text

Synthesis, In Vitro and In Vivo Evaluation, and Radiolabeling of Aryl Anandamide Analogues as Candidate Radioligands for In Vivo Imaging of Fatty Acid Amide Hydrolase in the Brain

Journal of Medicinal Chemistry ◽

10.1021/jm900324e ◽

2009 ◽

Vol 52 (15) ◽

pp. 4613-4622 ◽

Cited By ~ 25

Author(s):

Leonie wyffels ◽

Giulio G. Muccioli ◽

Sylvie De Bruyne ◽

Lieselotte Moerman ◽

Johan Sambre ◽

...

Keyword(s):

Fatty Acid ◽

In Vivo Imaging ◽

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

In Vivo Evaluation ◽

Amide Hydrolase ◽

The Brain ◽

Fatty Acid Amide

Download Full-text

Brain permeant and impermeant inhibitors of fatty-acid amide hydrolase suppress the development and maintenance of paclitaxel-induced neuropathic pain without producing tolerance or physical dependence in vivo and synergize with paclitaxel to reduce tumor cell line viability in vitro

Pharmacological Research ◽

10.1016/j.phrs.2019.02.002 ◽

2019 ◽

Vol 142 ◽

pp. 267-282 ◽

Cited By ~ 3

Author(s):

Richard A. Slivicki ◽

Zhili Xu ◽

Sonali S. Mali ◽

Andrea G. Hohmann

Keyword(s):

Neuropathic Pain ◽

Fatty Acid ◽

Fatty Acid Amide Hydrolase ◽

Physical Dependence ◽

Acid Amide ◽

Tumor Cell Line ◽

Amide Hydrolase ◽

Fatty Acid Amide

Download Full-text

Design and synthesis of new carbamates as inhibitors for fatty acid amide hydrolase and cholinesterases: Molecular dynamic, in vitro and in vivo studies

Bioorganic Chemistry ◽

10.1016/j.bioorg.2021.104684 ◽

2021 ◽

Vol 109 ◽

pp. 104684

Author(s):

Mahdi Faal Maleki ◽

Hamid Nadri ◽

Mostafa Kianfar ◽

Najmeh Edraki ◽

Farhad Eisvand ◽

...

Keyword(s):

Fatty Acid ◽

Molecular Dynamic ◽

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

In Vivo Studies ◽

Design And Synthesis ◽

Amide Hydrolase ◽

Fatty Acid Amide

Download Full-text

Inhibition of Vascular Growth by Modulation of the Anandamide/Fatty Acid Amide Hydrolase Axis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316973 ◽

2021 ◽

Author(s):

Sarah Rieck ◽

Sofia Kilgus ◽

Johanna H. Meyer ◽

Hao Huang ◽

Lan Zhao ◽

...

Keyword(s):

Cell Cycle ◽

Endothelial Cells ◽

Fatty Acid ◽

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

Antiangiogenic Effect ◽

Amide Hydrolase ◽

Fatty Acid Amide

Objective: Pathological angiogenesis is a hallmark of various diseases characterized by local hypoxia and inflammation. These disorders can be treated with inhibitors of angiogenesis, but current compounds display a variety of side effects and lose efficacy over time. This makes the identification of novel signaling pathways and pharmacological targets involved in angiogenesis a top priority. Approach and Results: Here, we show that inactivation of FAAH (fatty acid amide hydrolase), the enzyme responsible for degradation of the endocannabinoid anandamide, strongly impairs angiogenesis in vitro and in vivo. Both, the pharmacological FAAH inhibitor URB597 and anandamide induce downregulation of gene sets for cell cycle progression and DNA replication in endothelial cells. This is underscored by cell biological experiments, in which both compounds inhibit proliferation and migration and evoke cell cycle exit of endothelial cells. This prominent antiangiogenic effect is also of pathophysiological relevance in vivo, as laser-induced choroidal neovascularization in the eye of FAAH −/− mice is strongly reduced. Conclusions: Thus, elevation of endogenous anandamide levels by FAAH inhibition represents a novel antiangiogenic mechanism.

Download Full-text

Assessment of NSAIDs as potential inhibitors of the fatty acid amide hydrolase I (FAAH-1) using three different primary fatty acid amide substrates in vitro

BMC Pharmacology and Toxicology ◽

10.1186/s40360-021-00539-1 ◽

2022 ◽

Vol 23 (1) ◽

Author(s):

Julius T. Dongdem ◽

Gideon K. Helegbe ◽

Kwame Opare-Asamoah ◽

Cletus A. Wezena ◽

Augustine Ocloo

Keyword(s):

Fatty Acid ◽

Fatty Acid Amide Hydrolase ◽

Rank Order ◽

Acid Amide ◽

Substrate Affinity ◽

Cox Inhibitors ◽

Fatty Acid Amides ◽

Hydrolysis Of ◽

Fatty Acid Amide

Abstract Background Pain relief remains a major subject of inadequately met need of patients. Therapeutic agents designed to treat pain and inflammation so far have low to moderate efficiencies with significant untoward side effects. FAAH-1 has been proposed as a promising target for the discovery of drugs to treat pain and inflammation without significant adverse effects. FAAH-1 is the primary enzyme accountable for the degradation of AEA and related fatty acid amides. Studies have revealed that the simultaneous inhibition of COX and FAAH-1 activities produce greater pharmacological efficiency with significantly lowered toxicity and ulcerogenic activity. Recently, the metabolism of endocannabinoids by COX-2 was suggested to be differentially regulated by NSAIDs. Methods We analysed the affinity of oleamide, arachidonamide and stearoylamide at the FAAH-1 in vitro and investigated the potency of selected NSAIDs on the hydrolysis of endocannabinoid-like molecules (oleamide, arachidonamide and stearoylamide) by FAAH-1 from rat liver. NSAIDs were initially screened at 500 μM after which those that exhibited greater potency were further analysed over a range of inhibitor concentrations. Results The substrate affinity of FAAH-1 obtained, increased in a rank order of oleamide < arachidonamide < stearoylamide with resultant Vmax values in a rank order of arachidonamide > oleamide > stearoylamide. The selected NSAIDs caused a concentration-dependent inhibition of FAAH-1 activity with sulindac, carprofen and meclofenamate exhibiting the greatest potency. Michaelis-Menten analysis suggested the mode of inhibition of FAAH-1 hydrolysis of both oleamide and arachidonamide by meclofenamate and indomethacin to be non-competitive in nature. Conclusion Our data therefore suggest potential for study of these compounds as combined FAAH-1-COX inhibitors.

Download Full-text