Researchers develop compound that blocks enzyme in endocannabinoid signaling pathway in the brain

By Sathya Achia Abraham

A team of researchers has developed a compound able to block the action of a key enzyme in the endocannabinoid signaling pathway of the brain, which results in reduced pain sensitivity and marijuana-like behavioral effects in mice, according to new findings published in Nature Chemical Biology.

The findings, published Nov. 23, help shed some light on the molecular mechanisms involved in the endocannabinoid system and may ultimately point investigators to possible new therapeutic targets for the treatment of pain. The endocannabinoid system regulates physiological processes such as appetite, pain sensation, inflammation and memory.

The collaborative study, led by The Scripps Research Institute, together with Virginia Commonwealth University School of Medicine researchers, employed a mouse model to examine the interaction between the enzyme monacylglycerol lipase (MAGL), and a compound developed by the team, JZL184.

A chemical reaction known as enzymatic hydrolysis governs endocannabinoid system signaling. Enzymatic hydrolysis causes a cascade of molecular events resulting in disruption in the system’s signaling. Previous studies indicate that MAGL may play a key role in hydrolyzing the naturally occurring cannabinoid 2-arachidonylglycerol (2-AG), which is responsible for activating cannabinoid receptors, CB1 and CB2 in the central nervous system and throughout the body. The team developed JZL184 as the first drug that selectively inhibits MAGL.

According to Aron Lichtman, Ph.D., associate professor in the VCU Department of Pharmacology and Toxicology and principal investigator on the VCU portion of the study, CB1 receptors are responsible for the psychoactive effects of marijuana as well as many of the therapeutic effects of cannabinoids. In contrast, stimulation of CB1 receptors has been shown to elicit anti-inflammatory effects in laboratory animals. Lichtman said that It is hypothesized that elevating endogenous cannabinoids by blocking enzymes controlling their degradation will elicit therapeutic effects, with minimal side effects associated with marijuana.

In this study, the team found that blocking MAGL with JZL184 led to a dramatic increase in 2-AG in the brain, resulting in decreased pain sensitivity and a subset of other marijuana-like effects in mice, which included decreases in both locomotor behavior and body temperature. The effects were mediated through a CB1 receptor mechanism of action because JZL184 was inactive in the CB1 receptor knockout mice, or normal mice, that were pretreated with a drug that blocked the CB1 receptors.

“The availability of JZL184 will provide investigators in the field of drug discovery an important compound to explore the role of 2-AG in pain and other important physiological functions. Our work provides proof of principle that the enzyme MAGL may be a novel therapeutic target to treat pain,” said Lichtman.

This work was supported by a grant from the National Institute of Health, the Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute, and the Skaggs Institute for Chemical Biology.

Lichtman collaborated with VCU researchers Lamont Booker, James J. Burston, Steven G. Kinsey, Ph.D., Joel E. Schlosburg, and Dana E. Selley, Ph.D.; and Benjamin F. Cravatt, Ph.D., principal investigator of the study, Jonathan Z. Long, and Weiwei Li from The Skaggs Institute for Chemical Biology and Department of Chemical Physiology at The Scripps Research Institute; and Franciso J. Pavon, Ph.D., Antonia M. Serrano, Ph.D., and Loren H. Parsons, Ph.D., from the Committee on the Neurobiology of Addiction at The Scripps Research Institute.