The interaction of fatty acid amide hydrolase (FAAH) inhibitors with an anandamide carrier protein using (19)F-NMR.
It has been reported that the endocannabinoid anandamide (AEA) binds to a class of fatty acid-binding proteins and serum albumin which can serve as carrier proteins and potentiate the cellular uptake of AEA and its intracellular translocation. Here, we employed (19)F nuclear magnetic resonance spectroscopy to study the interactions of serum albumin with two inhibitors of fatty acid amide hydrolase (FAAH), the enzyme involved in the deactivation of anandamide. We found that, for both inhibitors AM5206 and AM5207, the primary binding site on serum albumin is drug site 1 located at subdomain IIA. Neither inhibitor binds to drug site 2. While AM5207 binds exclusively to drug site 1, AM5206 also interacts with other fatty acid-binding sites on serum albumin. Additionally, AM5206 has an affinity for serum albumin approximately one order of magnitude higher than that of AM5207. The data suggest that interactions of FAAH inhibitors with albumin may provide added advantages for their ability to modulate endocannabinoid levels for a range of applications including analgesia, antiemesis, and neuroprotection.
Center for Drug Discovery, Department of Pharmaceutical Sciences, and Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Jianqin
J
Zhuang
De-Ping
DP
Yang
Spyros P
SP
Nikas
Jianhong
J
Zhao
Jianxin
J
Guo
Alexandros
A
Makriyannis
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D001095:Arachidonic Acids / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005461:Fluorine; D008024:Ligands; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D010647:Phenyl Ethers / Q000378:metabolism* / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011485:Protein Binding; D012710:Serum Albumin, Bovine / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D002352:Carrier Proteins; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005461:Fluorine; D008024:Ligands; D010647:Phenyl Ethers; D053284:Polyunsaturated Alkamides; D012710:Serum Albumin, Bovine; D000099252:Fatty Acid Amide Hydrolases; C559613:AM 5206; C078814:anandamide