In this new Research Spotlight feature, a faculty member’s research will be highlighted each month. From research of discovery to application, the exciting work of our faculty has the potential to touch our lives. Our first spotlight features Dr. Bob Moore whose research is focused in cannabinoid based therapeutics.
Educational background: BS Chemistry/Physics, MS Chemistry with focus on biochemistry, PhD Medicinal Chemistry, Post-doc structural biology
Current position: Professor Pharmaceutical Sciences
Dr. Moore has been working in the area of cannabinoid based therapeutics for over 15 years.
Why did you choose to research this topic?
The therapeutic potential of cannabinoid therapeutics extends into a spectrum of diseases including inflammation, cancer, osteoporosis, pain, diabetes, and nausea/vomiting, to name a few. One of the major challenges to the field is dissecting out the adverse psychotropic effects associated with activation of the CB1 receptor in the brain. The most promising approach for regulating inflammation and immune response is to design compounds selective to the CB2 receptor in order to avoid these psychotropic side effects.
In 2008, while researching the potential of cannabinoids as anti-cancer drugs, we discovered that an intermediate in the synthesis of our trial cannabinoid series (SMM-189) was in fact was a selective CB2 inverse agonist. I had recently initiated a project to investigate the anti-inflammatory activity of cannabinoids. I decided to test the efficacy of SMM-189 in preventing inflammatory responses in stimulated human primary macrophages, endothelial, and epithelial cells. I was pleased to find that SMM-189 exhibited good anti-inflammatory properties and planned to test the compound for protective effects in the lung inquiry models. However, that all changed when an associate at the time asked me if the drug would be useful for treating multiple sclerosis; it turned out his wife was afflicted with the disease. I researched the pathology of the disease and learned that neuroinflammation is a key mediator in neurodegenerative diseases. Nor wanting to miss a potential opportunity, the anti-inflammatory studies were repeated using primary human microglia. The decision to venture into a new area was risky but well worth it. SMM-189 suppressed the inflammatory response in stimulated microglia. I immediately recognized the therapeutic potential of CB2 inverse agonists in treating a spectrum of neurodegenerative diseases.
The first test of the concept of regulating neuroinflammation using SMM-189 began between 2012-2013. In collaboration with Drs. Tony Reiner and Detlef Heck (Department of Anatomy and Neurobiology), we demonstrated that SMM-189 is highly effective in reversing adverse outcomes in mild traumatic brain injury. The successful proof of principle that CB2 inverse agonists effectively regulate neuroinflammation led to a new collaboration with Dr. Maul Tansey at Emory University who is currently evaluating the compound in Parkinson’s disease. At UT, we are currently seeking funding to extend our concept of neuroinflammation regulation into Alzheimer’s disease.
(Int J Mol Sci. 2014 Dec 31;16(1):758-87, Pharmacol Res Perspect. 2015 Aug;3(4):e00159).
What impact do you think this will have on patient care and pharmacy practice?
Interventions for neurodegenerative disorders represent a current unmet need in clinical practice. The Alzheimer’s Association estimates that in 2012 the cost for caring for patients was $200 billion per year and Parkinson’s is estimated to cost $23 billion per year. A therapy to slow or halt the progression of neurodegenerative disorders will significantly impact the quality of life for patients. In sum, the successful development of our lead compound SMM-189 will provide new hope for patients of neurodegenerative disorders and reduce the long-term cost for treating the diseases.
What obstacles have you encountered during your research and how did you overcome them?
Early on the biggest obstacle was the general perception that cannabinoids are synonymous with marijuana, which is anything but the case. The development of a CB2 inverse agonist is the most recent challenge, in part due to our limited understanding of the biological consequences of G-protein coupled receptor inverse agonists. Obtaining funding to develop a CB2 inverse agonist has been challenging; however, a firm belief in this novel approach and persistence towards the goal have been the key traits to overcome these obstacles.
What further research do you feel can be undertaken in this subject?
SMM-189 is a lead compound; in the future, we will optimize the chemical structure to improve the biopharmaceutical properties and enhance the potency and efficacy of this class of drugs. Drug development and testing of SMM-189, and future analogs, in models of Alzheimer’s, amyotrophic lateral sclerosis (ALS), and chronic traumatic encephalopathy (CTE) will be essential in advancing this therapeutic approach to treat neurodegenerative diseases.
What other areas of research are you interested in?
Chronic inflammation is an underlying pathology in many disease states. Another area where an intervention to treat chronic inflammation is an unmet need is periodontal disease. An ongoing project with the College of Dentistry is evaluating cannabinoid based therapies in periodontal disease. We are currently testing the hypothesis that CB2 based ligands will be efficacious in regulating chronic inflammation associated with infectious agents such as P. gingivalis. Additionally, the effects of selective CB2 ligands on the differentiation of progenitor cells to osteoblasts and cementoblasts are underway. It is hypothesized that CB2 inverse agonists will manifest dual activity by regulating inflammation and stimulating the production of new bone, which is another pathology in advanced periodontal disease.