Sumner Burstein, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Biochemistry and Molecular Pharmacology

Other Affiliation(s):
   Medicine

The Mechanism of Action of the Cannabinoids

Therapeutically Useful Cannabinoids
Interest in the cannabinoid acid metabolites of THC was revived recently by data we obtained showing that they exhibit some of the properties that are associated with nonsteroidal antiinflammatory agents (NSAIDs). The acids being non-psychoactive, were long thought to be without any biological actions of their own. In fact, our findings support the possibility that several effects believed to be due to THC may actually be mediated by the acid metabolites. In addition to helping explain the pharmacology of THC, our findings have suggested a route to the discovery of novel NSAIDs with minimal adverse side-effects, a much sought after goal of pharmaceutical research. Using THC-7-oic acid as a template molecule, we have designed and studied several dimethylheptyl side-chain analogs that show similar antiinflammatory properties, but at doses as low as 10 to 100µg/kg p.o. The most promising candidate has been named ajulemic acid which, in addition to its antiinflammatory actions, shows analgesic properties comparable to morphine in potency but devoid of the undesireable side effects. Ajulemic acid has recently been subjected by initial trials in humans based on its generally low toxicity in a variety of in vitro and animal models, and a Phase I trial where it showed no psychotropic activity. We have also found evidence for the existence of an endogenous cannabinoid acid, NAGly, that arises from the metabolism of anandamide, the endogenous THC. Like the THC acids, NAGly shows analgesic and anti-inflammatory activity.

Publications

Burstein S, Salmonsen R 2008. Acylamido analogs of endocannabinoids selectively inhibit cancer cell proliferation. Bioorg Med Chem doi:10.1016/j.bmc.2008.10.015.

Stebulis, Judith A., Johnson, David R., Rossetti, Ronald G., Burstein, Sumner H., Zurier, Robert B., Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells, Life Sciences (2008), doi: 10.1016/j.lfs.2008.09.004

Rimmerman N, Bradshaw HB, Hughes HV, Chen JS, Hu SS, McHugh D, Vefring E, Jahnsen JA, Thompson EL, Masuda K, Cravatt BF, Burstein S, Vasko MR, Prieto AL, O'Dell DK, Walker JM. N-Palmitoyl Glycine, a Novel Endogenous Lipid That Acts as a Modulator of Calcium Influx and Nitric Oxide Production in Sensory Neurons. Mol Pharmacol 2008.

Burstein, S. The elmiric acids: biologicaly active anandamide analogs, europharmacology (2007), doi: 10.1016/j.neuropharm.2007.11.011

Ambrosio, A. L., Dias, S. M., Polikarpov, I., Zurier, R. B., Burstein, S. H., Garratt, R. C., 2007. Ajulemic Acid, a Synthetic Nonpsychoactive Cannabinoid Acid, Bound to the Ligand Binding Domain of the Human Peroxisome Proliferator-activated Receptor {gamma}. J Biol Chem 282, 18625-18633.

Burstein, S. H., Adams, J. K., Bradshaw, H. B., Fraioli, C., Rossetti, R. G., Salmonsen, R. A., Shaw, J. W., Walker, J. M., Zipkin, R. E., Zurier, R. B., 2007. Potential anti-inflammatory actions of the elmiric (lipoamino) acids. Bioorg Med Chem 15, 3345-3355.

Johnson, D. R., Stebulis, J. A., Rossetti, R. G., Burstein, S. H., Zurier, R. B., 2007. Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid. J Cell Biochem 100, 184-190.

M. G. Cascio, A. Minassi, A. Ligrest, G. Appendino, S. H. Burstein and V. Di Marzo M. G. Cascio, A. Minassi, A. Ligrest, G. Appendino, S. H. Burstein and V. Di Marzo A structure activity relationship study on N-arachidonoyl-aminoacids as possible endogenous inhibitors of fatty acid amide hydrolase. Biochem Biophys Res Commun. (2004) 30; 314(1): 192-6.

M.Karst, K.Salim, S.Burstein, I.Conrad, L.Hoy and U.Schneider. (2003) Analgesic effect of the synthetic cannabinoid 1`,1`dimethylheptyl-delta⁸-THC-11-oic acid (CT-3) on chronic neuropathic pain in man. JAMA  290(13):1757-1762

Bidinger B, Torres R, Rossetti RG, Brown L, Beltre R, Burstein S, Lian JB, Stein GS, Zurier RB. Ajulemic acid. A non psychoactive cannabinoid acid, induces apoptosis in human T lymphocytes. (2003) Clin Immunol. 108(2):95-102.

J. Liu, H. Li, S. H. Burstein, J. D. Chen. (2003) Ajulemic Acid, a synthetic non-psychoactive cannabinoid, is an Activator for Peroxisome Proliferator-Activated Receptor g. Mol Pharmacol.63: 983-992

S. H. Burstein, S. M. Huang,T. J. Petros, R. G. Rossetti, J.M. Walker and R. B. Zurier. (2002) Regulation of anandamide tissue levels by N-arachidonylglycine. Biochem Pharmacol 64:1147-50.

R. B. Zurier, R.G. Rossetti, S. H. Burstein and B. Bidinger. Suppression of human monocyte Interleukin-1bproduction by ajulemic acid, a non-psychoactive cannabinoid. (2003) Biochem Pharmacol. 65: 649-655

L.D.Recht ,R. Salmonsen ,R. Rosetti., T. Jang ,G. Pipia , T. Kubiatowski , P. Karim., A. H. Ross , R. Zurier, N.S. Litofsky, S. Burstein.Antitumor Effects of Ajulemic Acid (CT3), a synthetic non-psychoactive cannabinoid, Biochem. Pharmacol. 62: 755-763 (2001).

S. Huang SM, Bisogno T, Petros TJ, Chang SY, Zavitsanos PA, Zipkin RE, Sivakumar R, Coop A, Maeda DY, De Petrocellis L, Burstein S, Di Marzo V and Walker JM (2001) Identification of a New Class of Molecules, the Arachidonyl Amino Acids, and Characterization of One Member That Inhibits Pain. J Biol Chem. 276:42639-42644.

Academic History

BS, Massachusetts Institute of Technology, 1953
PhD, Wayne State University, 1959 Postdoctoral Training
Fellow, Weizmann Institute, 1960
Fellow, Brandeis University, 1961

Office: Research 803, Lab 870W
Phone: 508-856-2850
E-mail: Sumner.Burstein@umassmed.edu

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