Synthesis and pharmacological evaluation of 2,4-dinitroaryldithiocarbamate derivatives as novel monoacylglycerol lipase inhibitors.
Monoacylglycerol lipase (MAGL) is responsible for signal termination of 2-arachidonoylglycerol (2-AG), an endocannabinoid neurotransmitter endowed with several physiological effects. Previously, we showed that the arylthioamide scaffold represents a privileged template for designing MAGL inhibitors. A series of 37 compounds resulting from pharmacomodulations around the arylthioamide template were synthesized and tested to evaluate their inhibitory potential on MAGL activity as well as their selectivity over fatty acid amide hydrolase (FAAH), another endocannabinoid-hydrolyzing enzyme. We have identified 2,4-dinitroaryldithiocarbamate derivatives as a novel class of MAGL inhibitors. Among the synthesized compounds, we identified [2,4-dinitrophenyl-4-(4-tert-butylbenzyl)piperazine-1-carbodithioate] (CK37), as the most potent MAGL inhibitor within this series (IC(50) = 154 nM). We have also identified [2,4-dinitrophenyl-4-benzhydrylpiperazine-1-carbodithioate] (CK16) as a selective MAGL inhibitor. These compounds are irreversible MAGL inhibitors that probably act by interacting with Cys208 or Cys242 and Ser122 residues of the enzyme. Moreover, CK37 is able to raise 2-arachidonoylglycerol (2-AG) levels in intact cells.
Medicinal Chemistry, Cannabinoid and Endocannabinoid Research Group, B1.73.10, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, 73 Avenue E. Mounier, B-1200 Bruxelles, Belgium.
Coco N
CN
Kapanda
Julien
J
Masquelier
Geoffray
G
Labar
Giulio G
GG
Muccioli
Jacques H
JH
Poupaert
Didier M
DM
Lambert
D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004220:Disulfides / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
C574772:2,4-dinitrophenyl-4-(4-tert-butylbenzyl)piperazine-1-carbodithioate; D002219:Carbamates; D004220:Disulfides; D004791:Enzyme Inhibitors; D010879:Piperazines; D008994:Monoacylglycerol Lipases; D013890:Thiourea