There is a growing but controversial interest in medicinal use of cannabis. Cannabis produces psychotropic effects, is federally illegal in the US, and adequate regulation of quality, safety and efficacy of cannabis products is lacking. Therefore, novel drugs acting similarly to Δ9-tetrahydrocannabinol (Δ9-THC), the primary active ingredient in cannabis, but with reduced adverse effects are needed. Δ9-THC acts at CB1 and CB2 cannabinoid receptors. Consequently, the purpose of this dissertation was to provide pre-clinical pharmacodynamic data to develop novel classes of cannabinoids derived from the indole quinuclidine (IQD) and selective estrogen receptor modulator (SERM) scaffolds.
Several IQD analogues were reported to bind with high affinity to cannabinoid receptors, with unknown activity. Therefore, in Aim one of this dissertation, the intrinsic activity of eleven IQD compounds was examined at CB1 and CB2 receptors. At CB1 receptors, one analogue demonstrated agonist activity, eight acted as neutral antagonists, and two exhibited inverse agonist activity. Concerning CB2 receptors, nine analogues were agonists and two acted as inverse agonists. Potencies of all IQDs were consistent with the affinity of each analogue for cannabinoid receptors. The SERM tamoxifen has been reported to bind non-selectively to cannabinoid receptors with moderate affinity. Therefore, experiments in Aim two of this dissertation characterized the affinity and activity of fourteen SERMs from five structurally distinct classes at CB1 and/or CB2 receptors. SERMs belonging to four of the five classes exhibited high affinity, bound selectively to either CB1 and/or CB2 receptors and acted as inverse agonists.
The SERM scaffold is being used to develop drugs with decreased affinity for estrogen receptors (ERs) that retain anti-cancer activity, known as the ridaifen compounds. A first generation compound, ridaifen-B (RID-B), was examined in Aim three of this project. RID-B was 17-fold selective for binding to CB 2 over CB1 receptors, and acted as an inverse agonist. RID-B also exhibited anti-inflammatory and anti-osteoclastogenic effects.
Collectively, evidence was presented for development of two novel classes of cannabinoid ligands from the IQD and SERM scaffolds. Additional rounds of optimization should lead to drugs that act at cannabinoid receptors with improved safety profile relative to Δ9-THC.
|Advisor:||Prather, Paul L.|
|Commitee:||Borrelli, Michael J., Gottschall, Paul E., Kadlubar, Susan A., MacMillan-Crow, Lee Ann|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Keywords:||Agonist, Cannabinoid, Drug development, G-protein coupled receptor, Inverse agonist, Serm|
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