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Dissertation/Thesis Abstract

Characterization of allosteric modulators of CB2 receptors as novel therapeutics for inflammatory diseases
by Rajasekaran, Maheswari, Ph.D., University of Arkansas for Medical Sciences, 2011, 195; 3454568
Abstract (Summary)

Cannabinoids produce anti-inflammatory effects by acting at CB1 and CB2 receptors. Drugs selectively activating non-neuronal CB2 receptors avoid CB1-mediated adverse effects. However, chronic use of direct acting CB2 receptor agonists is also associated with limitations that may be overcome by employing allosteric modulators (AMs). AMs bind to allosteric sites, which are topographically distinct from orthosteric sites (binding sites for endogenous agonists) and alter receptor conformation to increase or decrease the function of endogenous or synthetic ligands acting concurrently at orthosteric sites. No AMs have been reported for CB2 receptors. Therefore, the purpose of the studies described in this dissertation was to identify novel AMs for CB2 receptors.

In chapter one, trans-β-caryophyllene (TBC), a dietary compound that has recently been reported to produce in vivo anti-inflammatory effects via CB2 receptors was examined. TBC displayed characteristics of an AM by altering the dissociation kinetics of orthosteric ligands in a probe-dependent manner. However, in functional assays, TBC produced little modulatory effect on the ability of CB2 orthosteric ligands to regulate adenylyl cyclase (AC) enzyme and did not alter survival intervals of G93A-SOD1 mice, a model of ALS. In chapter two, while investigating potential cannabinoid actions of gambogic acid (GA) (a phytochemical that exhibits pro-apoptotic and anti-inflammatory properties similar to CB2 receptor agonists), it was observed that the GA derivative gambogic acid amide (GAA) exhibited binding characteristic consistent with that of an AM. Further characterization confirmed that GAA acted as an AM to alter the dissociation kinetics and function of CB2 orthosteric ligands in a probe-dependent manner. In the cecal ligation and puncture (CLP) model of sepsis, GAA also reduced serum levels of several inflammatory cytokines. Chapter three sought to identify additional AMs of CB2 receptors with higher affinity and/or potency than GAA. This was accomplished by quantifying the allosteric modulatory activity of several structurally related GA derivatives. Specifically, these studies demonstrated that dihydro GA and garcinolic acid acted as negative and positive AMs of CB2 receptors, respectively. In the CLP sepsis model, garcinolic acid displayed anti-inflammatory effects.

Taken collectively, these studies importantly confirm the presence of an AM site on CB2 receptors. Furthermore, data presented suggest that the structures of GA and TBC will provide beginning scaffolds for the design of more potent and efficacious AMs for CB2 receptors to treat inflammatory disorders.

Indexing (document details)
Advisor: Prather, Paul L.
Commitee: Drew, Paul D., Mayeux, Philip R., McGehee, Robert E., Wessinger, William D.
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Biomedical Sciences
School Location: United States -- Arkansas
Source: DAI-B 72/08, Dissertation Abstracts International
Subjects: Pharmacology
Keywords: Allosteric modulators, CB2 receptors, Caryophyllene, Inflammatory diseases, Orthosteric ligands
Publication Number: 3454568
ISBN: 978-1-124-64323-6
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