The primary goal of this proposal is to design and synthesize novel 2-arachidonoylglycerol analogs (2-AG) with improved potency and biochemical stability as pharmacological probes for key endocannabinoid targets. The most successful of the resulting new ligands will contribute our understanding of the role of 2- arachidonoylglycerol (2-AG) in endocannabinoid signaling and its influence on appetite, substance abuse, and other (patho)physiological processes. The first objective involves synthesis of metabolically stable analog of 2- AG, as endogenous 2-AG undergoes spontaneous enzymatic degradation and acyl migration. The proposed structural features include: (a) increasing stability of ester by introducing (i) steric hindrance and (ii) bioisosteres and (b) modifying chain to mimic lipophilic chain of arachidonic acid (including various substituted phenyl, biphenyls, diphenylmethane and oxydibenzene) (c) The second objective is to develop a covalent probe exploring the ligand binding motifs involved in the activation of the cannabinoid receptors (CB1 and CB2) by their endogenous ligand, 2-AG. These newly synthesized 2-AG analogs will be assayed for their affinity to the cannabinoid receptors CB1 and CB2 as well as inhibition of endocannabinoid proteins: monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), the putative endocannabinoid transporter system. The lack of stable 2-AG analogs represents a significant void in the research tools available to dissect the endocannabinoid system and study its delicate balance with lipid metabolism, calcium ion transport, inflammation, cell signaling, and reward mechanisms in the brain. The downregulation of the endocannabinoid system is particularly important for medical conditions related to overstimulation of the cannabinoid receptor including recovery from substance abuse, obesity, and movement disorders.

Public Health Relevance

The endocannabinoid system is involved in cell signaling which affect pain, hunger, and cravings for drugs of abuse. A number of currently popular medications antagonize the endocannabinoid receptor proteins and the goal of this proposal is to design and synthesize novel 2-arachidonoylglycerol analogs (2-AG) with improved potency and biochemical stability as pharmacological probes for key endocannabinoid targets. The most successful of the resulting new ligands will contribute our understanding of the role of 2-arachidonoylglycerol (2-AG) in endocannabinoid signaling and its influence on appetite, substance abuse, and other (patho)physiological processes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
1R03DA029184-01
Application #
7875958
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (91))
Program Officer
Hillery, Paul
Project Start
2010-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$194,531
Indirect Cost
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Whitten, Kyle M; Makriyannis, Alexandros; Vadivel, Subramanian K (2012) Enzymatic synthesis of N-Acylethanolamines: Direct method for the aminolysis of esters. Tetrahedron Lett 53:5753-5755
Whitten, Kyle M; Makriyannis, Alexandros; Vadivel, Subramanian K (2012) Application of Chemoenzymatic Hydrolysis in the Synthesis of 2-Monoacylglycerols. Tetrahedron 68:5422-5428
Vadivel, Subramanian K; Whitten, Kyle M; Makriyannis, A (2011) Chemoenzymatic Synthesis of 2-Arachidonoylglycerol, An Endogenous Ligand for Cannabinoid Receptors. Tetrahedron Lett 52:1149-1150
Duclos Jr, Richard I; Johnston, Meghan; Vadivel, Subramanian K et al. (2011) A methodology for radiolabeling of the endocannabinoid 2-arachidonoylglycerol (2-AG). J Org Chem 76:2049-55