| The endocannabinoid system is a complex homeostatic signaling system controlled through the actions of two G-protein coupled receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Significant neuronal expression and distribution of CB1 throughout the brain establishes its function as a major synaptic signaling receptor, and in regards to the actions of Cannabis sativa, it is the primary mediator of the psychotropic effects of marijuana. Conversely, CB2 expression is confined to microglial cells in the brain and predominantly peripheral immune cells. The expression of CB2 provides a pharmacological basis for the well-documented immunomodulatory effects of cannabis, providing a potential therapeutic target for the treatment of diseases involving immune function. Through careful isolation and characterization, the active constituents of cannabis were eventually revealed as a unique class of natural products, the cannabinoids, the most prolific of which is (-)-Delta9-tetrahydrocannabinol.;This aim of this dissertation research is to utilize a natural product cannabinoid as a starting point in the development of synthetic cannabinoid receptor ligands. The discovery of the THC analog (-)-Delta9-10a-alpha-hydroxytetrahydrocannabinol (10a-OH THC) provided a molecular framework from which a benzofuran scaffold was hypothesized to provide opportunities to include most of the pharmacophoric elements of 10a-OH THC. Target molecules were designed to maximally explore the chemical space of this new scaffold to elucidate a structure activity relationship, culminating in the discovery of an analog with 78.4 nM affinity and 28-fold selectivity for the CB2 receptor. The synthetic analogs described herein serve as lead molecules for further synthesis and optimization of cannabinoid receptor activity, potentially contributing interesting new drug leads for CB2 receptor targeting therapeutics. |
