Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to the cannabinoid receptor.
Arachidonoyl ethanolamide (anandamide) is an endogenous ligand for cannabinoid receptors (CB1, CB2) and a putative neurotransmitter. Phenylmethylsulfonyl fluoride (PMSF) is an inhibitor of the enzyme (an amidase) which hydrolyzes anandamide to arachidonic acid and ethanolamine. We report here that fatty acid sulfonyl fluorides are potent inhibitors of anandamide metabolism. In order to investigate the SAR of these anandamide amidase inhibitors we tested a series of fatty acid (C12 to C20) sulfonyl fluorides both as inhibitors of anandamide degradation and as ligands for the central cannabinoid receptor (CB1). AM374 (palmitylsulfonyl fluoride, C16) was approximately 20 times more potent than PMSF and 50 times more potent than arachidonyltrifluoromethyl ketone in preventing the hydrolysis of anandamide in brain homogenates. AM374 was over a thousand-fold more effective than PMSF in inhibiting the amidase in cultured cells. The C12 to C18 sulfonyl fluoride analogs were equipotent as inhibitors of the amidase and the reverse reaction (the synthase) with nanomolar IC50 values. These compounds generally showed decreasing affinity for the CB1 receptor as the chain length increased; thus, C12 sulfonylfluoride had an IC50 of 18 nM and C20 sulfonylfluoride had an IC50 of 78 microM. The C14, C16, and C18 sulfonyl fluorides showed high selectivity for the amidase over the CB1 receptor and thus are potentially useful selective anandamide amidase inhibitors.
Deutsch
D G
DG
Department of Biochemistry and Cell Biology, State University of New York at Stony Brook 11794, USA.
Lin
S
S
Hill
W A
WA
Morse
K L
KL
Salehani
D
D
Arreaza
G
G
Omeir
R L
RL
Makriyannis
A
A
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism; D010168:Palmitates / Q000737:chemistry / Q000494:pharmacology*; D010664:Phenylmethylsulfonyl Fluoride / Q000031:analogs & derivatives / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C104963:AM 374; D001095:Arachidonic Acids; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D010168:Palmitates; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013450:Sulfones; D010664:Phenylmethylsulfonyl Fluoride; D000581:Amidohydrolases; C087226:arachidonoylethanolamide synthase; C078814:anandamide