Synthesis and Biological Evaluation of Cannabinoid Receptor Ligands

Cole, Mariah Leigh (2017) Synthesis and Biological Evaluation of Cannabinoid Receptor Ligands. Undergraduate thesis, under the direction of John Rimoldi from Biomolecular Sciences, University of Mississippi.

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Abstract

The cannabinoid receptors, members of the G-protein coupled receptor (GPCR) superfamily, have been implicated in numerous human physiological functions and diseases. These receptors, cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2), are most concentrated in the central nervous system and immune cells, respectively, and have each become a target of therapeutic interest. Dual CB1/CB2 agonists such as delta-9-tetrahydrocannbinol (THC) have demonstrated efficacy in the treatment of nausea, pain, and glaucoma, but suffer from psychotropic effects mediated by CB1, motivating the search for CB2 selective therapeutic agents. Selective modulation of the CB2 receptor has therapeutic potential in human health disorders such as pain, inflammation, and cancer. In our efforts to develop CB2 receptor selective ligands, we preliminarily examined a structure activity relationship (SAR) study of synthetic and natural terpenoid cannabinoids to design more potent and selective CB receptor ligands. In an effort to expand this SAR, we synthesized a series of analogs with alternative functional groups and substitution patterns using a dihydrobenzofuran scaffold, with previous biological assay data guiding the design of our new compounds. Aldol condensation and Luche reduction reactions were used to create six new analogs. The structures of the new analogs synthesized were confirmed using NMR and MS techniques. The compounds were submitted for biological evaluation in a radioligand displacement assay for both the CB1 and CB2 receptors. One compound exhibited modest affinity for the CB2 receptor. The alterations in functional groups and substitution patterns provided analog data to help create a more comprehensive structure activity relationship study in the future development of CB2 selective compounds. This research was funded by Grant Number P20GM104931 from the National Institute of General Medical Sciences (NIGMS), COBRE-NPN.

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