Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets.
Fatty acid amide hydrolase (FAAH) is the primary regulator of several bioactive lipid amides including anandamide. Inhibitors of FAAH are potentially useful for the treatment of pain, anxiety, depression, and other nervous system disorders. However, FAAH inhibitors must display selectivity for this enzyme relative to the numerous other serine hydrolases present in the human proteome in order to be therapeutically acceptable. Here we employed activity-based protein profiling (ABPP) to assess the selectivity of FAAH inhibitors in multiple rat and human tissues. We discovered that some inhibitors, including carbamate compounds SA-47 and SA-72, and AM404 are exceptionally selective while others, like URB597, BMS-1, OL-135, and LY2077855 are less selective, displaying multiple off-targets. Since proteins around 60kDa constitute the major off-targets for URB597 and several other FAAH inhibitors with different chemical structures, we employed the multi-dimensional protein identification technology (MudPIT) approach to analyze their identities. We identified multiple carboxylesterase isozymes as bona fide off-targets of FAAH inhibitors. Consistently, enzymatic assay confirmed inhibition of carboxylesterase activities in rat liver by FAAH inhibitors. Since carboxylesterases hydrolyze a variety of ester-containing drugs and prodrugs, we speculate that certain FAAH inhibitors, by inhibiting carboxylesterases, might have drug-drug interactions with other medicines if developed as therapeutic agents.
Zhang
Di
D
Neuroscience Research, Advanced Technology and Process Research and Development, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. di.zhang@abbott.com
Saraf
Anita
A
Kolasa
Teodozyi
T
Bhatia
Pramila
P
Zheng
Guo Zhu
GZ
Patel
Meena
M
Lannoye
Greg S
GS
Richardson
Paul
P
Stewart
Andrew
A
Rogers
John C
JC
Brioni
Jorge D
JD
Surowy
Carol S
CS
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002219:Carbamates / Q000494:pharmacology*; D043182:Carboxylesterase / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D020543:Proteome / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014162:Transfection / Q000379:methods; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000906:Antibodies; D001549:Benzamides; D002219:Carbamates; D043182:Carboxylesterase; D004791:Enzyme Inhibitors; D020543:Proteome; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester