The endocannabinoid system is a signaling network in the brain and periphery that plays a role in maintaining the balance of many of our physiological functions, including sleep, appetite, pain, memory, and mood. The system is also the target of the psychoactive substance in the cannabis plant, tetrahydrocannabinol (THC), which produces its effects through activation of two cannabinoid receptors, CB1 and CB2. In the brain, CB1 activation reduces excessive neurotransmission, while CB2 activation reduces inflammatory signaling. The naturally occurring activators of the cannabinoid receptors are the endogenous cannabinoids, or endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG).
Since the discovery of the endocannabinoid system, researchers have made significant advances in understanding the role it plays in health and disease. Neurological disorders, such as multiple sclerosis, Tourette Syndrome, Alzheimer’s disease, epilepsy, ADHD, and pain, have seen few major treatment advances and are natural areas of exploration for molecules that target the endocannabinoid system. However, the scientific community is only just beginning to identify how to safely manipulate the endocannabinoid system to modify disease and provide therapeutic benefit. Some researchers are seeking to achieve this with cannabis-based products – after all, the therapeutic benefit of cannabis has been well-recognized for centuries in patients suffering from a wide variety of ailments. Appropriate and precise delivery of therapeutically active doses of cannabis, however, is a challenge. In addition, cannabinoids act indiscriminately, activating every accessible cannabinoid receptor pathway in the body, which can cause severe side effects. As a result, it would be wise for the industry to consider alternative molecules, such as those that amplify the action of the body’s own endocannabinoids by preventing their enzymatic degradation. This is something Abide Therapeutics has been focusing on. We have combined our activity-based protein profiling platform with a library of structurally unique small molecules to help identify previously inaccessible drug targets within the under-explored serine hydrolase superfamily, which act through the endocannabinoid pathway. Using this approach, we have developed ABX-1431 (in collaboration with Celgene, which holds ex-US rights to ABX-1431). ABX-1431 is an oral, first-in-class inhibitor of monoacylglycerol lipase (MGLL) with the potential to treat neurological disorders, pain and neuroinflammation. MGLL is responsible for terminating endocannabinoid signaling by breaking down the primary endocannabinoid, 2-AG. The inhibition of MGLL results in increased 2-AG levels, enhanced signaling through the cannabinoid receptors, and regulation of neurotransmission and inflammation. Preclinical studies conducted so far demonstrate that ABX-1431 mimics the beneficial therapeutic effects of cannabis without negatively affecting cognition or behavior, due to its specificity towards MGLL and effects on CB1 receptors in active signaling pathways. The drug was generally well tolerated and there were no serious adverse events. Preliminary data from an ongoing PET occupancy study indicate dose-related brain penetrance of orally-administered ABX-1431 using ABX-1488, an Abide proprietary, MGLL-specific PET ligand. The molecule is now being studied in a variety of patient populations.
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