Dissertation/Thesis Abstract

Cannabinoid receptor inverse agonists as novel therapeutic agents
by Seely, Kathryn A., Ph.D., University of Arkansas for Medical Sciences, 2009, 170; 3357550
Abstract (Summary)

The purpose of these studies was to investigate cannabinoid receptor inverse agonists, which decrease the constitutive activity of cannabinoid receptors, as innovative therapies and explore unique interactions of these compounds with μ-opioid receptors (MOR).

Amyotrophic lateral sclerosis (ALS) is a neuroinflammatory disease characterized by degeneration of spinal motor neurons. During ALS, CB2 receptors, localized on immune cells, are up-regulated within the spinal cord, indicating a prospective drug target. Since multiple drugs acting by different and distinct mechanisms may be superior treatments, curcumin, a polyphenol in the spice turmeric with anti-inflammatory and anti-oxidant properties, may also represent a novel ALS treatment. The results suggested CB2 inverse agonists prolong survival longer than vehicle treated controls. Also, curcumin lengthens survival but concurrent treatment with curcumin and CB2 inverse agonists antagonize each treatment alone. Therefore, CB2 inverse agonists and curcumin may be novel ALS treatments but concurrent treatment of these compounds should be avoided.

Since curcumin and CB2 inverse agonists appeared to antagonize each other, we investigated the binding of curcumin and other polyphenols, such as trans-resveratrol in red wine, to cannabinoid receptors. Surprisingly, these polyphenols bind CB1 receptors, the most abundant G-protein coupled receptor in the central nervous system, selectively with nanomolar affinity and act as antagonists/inverse agonists. Importantly, curcumin and tran-resveratrol produce weight loss similar to a CB1 inverse agonist control suggesting the potential development of polyphenols as anti-obesity treatments.

Lastly, a recent study demonstrated a CB1 inverse agonist enhanced MOR function suggesting the constitutive activity of CB1 receptors modulates the function of MOR. Therefore, we investigated the interaction of CB1 and MOR using AM251, a CB1 selective inverse agonist. The results suggest that interactions between AM251 and MOR are not entirely mediated by CB1/MOR interactions because AM251 binds directly to MOR as an antagonist with nanomolar affinity. Therefore, AM251 modulation of MOR may be occurring via AM251 binding directly to MOR as well as interactions between CB1 and MOR.

Overall, these studies suggest that cannabinoid receptor inverse agonists may be developed as novel therapeutic options for many diseases, such as ALS and obesity.

Indexing (document details)
Advisor: Prather, Paul L.
Commitee:
School: University of Arkansas for Medical Sciences
School Location: United States -- Arkansas
Source: DAI-B 70/04, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Neurosciences, Pharmacology
Keywords: ALS, Amyotrophic lateral sclerosis, Cannabinoids, Opioids, Polyphenols
Publication Number: 3357550
ISBN: 9781109148268
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