Transporters (carriers, chaperones) for the endocannabinoid, anandamide (AEA) have recently been identified. One class of these transporters are the fatty acid binding proteins (FABPs). The FABPs are a family of small soluble carrier proteins for lipophilic substances. These FABPs have recently been shown to """"""""solubilize"""""""" anandamide so it can move inside the cell for degradation by enzymes at the endoplasmic reticulum. The major goal of this proposal is to develop drugs that bind to these anandamide carriers. We hypothesize that targeting these FABPs with inhibitors will prevent anandamide being transported for breakdown inside the cell and subsequently raise the extracellular levels of anandamide, resulting in anti-nociceptive and anti-inflammatory effects. We will test this hypothesis by identifying and designing inhibitors of the anandamide transporters. This approach will involve a combination of interrelated techniques including in silico screening of commercial drug libraries using DOCK followed by re- ranking with a novel footprint-based scoring function. The most promising compounds will then be tested employing a fluorescent displacement assay for their ability to bind mainly to FABP5 and FABP7 that occur in the nervous system. From these binding data, chemical synthesis of lead compounds will be undertaken to authenticate their structure. The most promising compounds will be tested in cell culture uptake assays, engineered to contain specific FABPs. The best transport inhibitors will be tested for efficacy in mice using models of pain and inflammation. Finally, X-ray crystallographic structures of a select number of the aforementioned FABP-inhibitor complexes will be determined. This X-ray data will be employed for more accurate in silico screening and for the chemical synthesis of more potent and specific FABP inhibitors. Anandamide transport inhibitors found in this fashion may lead to novel approaches for treatment of pain and inflammation and eventually to medications for drug abuse and addiction. Our preliminary studies have identified a class of compounds, the """"""""truxilloids"""""""", that are anti-nociceptive and anti inflammatory in mice.

Public Health Relevance

Anandamide is a neurotransmitter that occurs naturally throughout the body for regulation of pain and stress. We have designed a way to raise anandamide levels, using newly identified compounds that binds to the recently discovered anandamide transporter. In this manner it will be possible to develop new drugs for pain, stress and issues with drug addiction and withdrawal.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Hillery, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University New York Stony Brook
Schools of Arts and Sciences
Stony Brook
United States
Zip Code
Peng, Xiaoxue; Studholme, Keith; Kanjiya, Martha P et al. (2017) Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms. Mol Pain 13:1744806917697007
Allen, William J; Fochtman, Brian C; Balius, Trent E et al. (2017) Customizable de novo design strategies for DOCK: Application to HIVgp41 and other therapeutic targets. J Comput Chem 38:2641-2663
Hsu, Hao-Chi; Tong, Simon; Zhou, Yuchen et al. (2017) The Antinociceptive Agent SBFI-26 Binds to Anandamide Transporters FABP5 and FABP7 at Two Different Sites. Biochemistry 56:3454-3462
Martin, Gregory G; Chung, Sarah; Landrock, Danilo et al. (2016) FABP-1 gene ablation impacts brain endocannabinoid system in male mice. J Neurochem 138:407-22
Schroeder, Friedhelm; McIntosh, Avery L; Martin, Gregory G et al. (2016) Fatty Acid Binding Protein-1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias. Lipids 51:655-76
Thanos, Panayotis K; Clavin, Brendan H; Hamilton, John et al. (2016) Examination of the Addictive and Behavioral Properties of Fatty Acid-Binding Protein Inhibitor SBFI26. Front Psychiatry 7:54
Elmes, Matthew W; Kaczocha, Martin; Berger, William T et al. (2015) Fatty acid-binding proteins (FABPs) are intracellular carriers for ?9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem 290:8711-21
Azim, Syed; Nicholson, James; Rebecchi, Mario J et al. (2015) Endocannabinoids and acute pain after total knee arthroplasty. Pain 156:341-347
Sirrs, Sandra; van Karnebeek, Clara D M; Peng, Xiaoxue et al. (2015) Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms. Orphanet J Rare Dis 10:38
Kaczocha, Martin; Glaser, Sherrye T; Maher, Thomas et al. (2015) Fatty acid binding protein deletion suppresses inflammatory pain through endocannabinoid/N-acylethanolamine-dependent mechanisms. Mol Pain 11:52

Showing the most recent 10 out of 15 publications