Discovery of (E)-3-(4-(Diethylamino) phenyl)-1-phenyl-2-phenylsulfonyl)prop-2-en-1-one as Novel Cannabinoid Receptor 2 Ligands

Cannabinoids (CB) are defined as a class of compounds that can act on Cannabinoid receptors 1 or 2 (CB1 or CB2) and affect human physiology. Both CB1 and CB2 receptors belong to the rhodopsin-like family of G-Protein Coupled Receptors (GPCRs). However, CB1 receptor is mainly expressed in the central nervous system, while CB2 receptor is dominantly located in the peripheral nervous system and immune cells. By now, scientists have discovered many CB ligands that have therapeutic potentials, but the limitation of non-selective ligands is the psychiatric side effect mediated by the activation of CB1 receptor. Although CB1 receptor is crucial in analgesic and anti-inflammatory effects, strategies of designing CB2 selective ligands are made by medicinal chemists to avoid undesirable effects in clinic. In this thesis, we discovered novel CB2 lead compounds with new chemical scaffolds; designed and synthesized four series of analogues for the structure-activity relationship (SAR) studies; tested their binding affinity to both CB2 and CB1 receptors; conducted in-vitro functional studies; and evaluated their potentials for therapeutic treatment. In total, four series of (E)-3-(4-Ethoxy-3-methoxyphenyl)-2-((4-methoxyphenyl) sulfonyl)-1-phenylprop-2-en-1-one have been identified as novel cannabinoid ligands. Physicochemical properties were predicted and docking studies using our CB2 model was conducted. 29 derivatives were then synthesized to conduct SAR studies. The binding affinity and selectivity for cannabinoid receptor CB1 and CB2 were then evaluated. Four compounds showed high CB2 binding affinity (Ki of 10-60 nM) and good selectivity (CB1/CB2 of 20- to 1305 fold). Their off-targets effects were also predicted. Overall, these sulfone derivatives can be used to develop novel therapeutic CB2 ligands.