ABSTRACT
Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.
Subject(s)
Amides/pharmacology , Azetidines/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Monoacylglycerol Lipases/antagonists & inhibitors , Piperazines/pharmacology , Amides/chemistry , Azetidines/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Monoacylglycerol Lipases/metabolism , Piperazines/chemistry , Structure-Activity RelationshipABSTRACT
Inhibitors of both heat shock proteins Hsp90 and Hsp70 have been identified in assays measuring luciferase refolding containing rabbit reticulocyte lysate or purified chaperone components. Here, we report the discovery of a series of phenoxy-N-arylacetamides that disrupt Hsp70-mediated luciferase refolding by binding to DnaJ, the bacterial homolog of human Hsp40. Inhibitor characterization experiments demonstrated negative cooperativity with respect to DnaJ and luciferase concentration, but varying the concentration of ATP had no effect on potency. Thermal shift analysis suggested a direct interaction with DnaJ, but not with Hsp70. These compounds may be useful tools for studying DnaJ/Hsp40 in various cellular processes.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Escherichia coli Proteins/metabolism , HSP40 Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/antagonists & inhibitors , Luciferases/chemistry , Luciferases/metabolism , Adenosine Triphosphate/metabolism , Animals , Drug Evaluation, Preclinical , HSP70 Heat-Shock Proteins/metabolism , Humans , Inhibitory Concentration 50 , Protein Folding , RabbitsABSTRACT
We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.
Subject(s)
TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/metabolism , Tetrahydronaphthalenes/pharmacology , Urea/pharmacology , Binding, Competitive/drug effects , Cell Line , Drug Evaluation, Preclinical , Humans , Molecular Structure , Structure-Activity Relationship , TRPV Cation Channels/chemistry , Tetrahydronaphthalenes/chemistry , Urea/analogs & derivatives , Urea/chemistryABSTRACT
Using a 'directed' iodination procedure, novel iodo-resiniferatoxin congeners were synthesized from 4-acetoxy-3-methoxyphenylacetic acid and resiniferinol- 9,13,14-ortho-phenylacetate (ROPA). The 2-iodo-4-hydroxy-5-methoxyphenylacetic acid ester of resiniferinol 5 displayed high affinity binding (K(i)=0.71 nM) for the human vanilloid VR1 receptor and functioned as a partial agonist.