Development of Selective -Opioid Receptor Positive Allosteric Modulators for the Treatment of Depression

Abstract

Major depressive disorder is one of the three leading causes that reduce quality of life. Due to the comorbidity of major depressive disorder with anxiety and chronic pain, existing antidepressant drugs have limited effectiveness and often lead to adverse effects. There is an urgency for safer and more effective antidepressant therapeutics. The δ-opioid receptor (DOR), a member of the opioid receptor family, has been shown to be involved in mood regulation and chronic pain. In rats and mice, DOR agonists acting at the orthosteric site have antidepressant, anxiolytic, and analgesic effects, without the abuse liability of agonists acting at the μ-opioid receptor (MOR). Although the beneficial effects of DOR activation make it a plausible therapeutic target, activation of DOR leads to pro-convulsive activity; its agonists are also susceptible to profound tolerance. There is considerable interest in the development of DOR positive allosteric modulators (PAMs). By binding to the distinct location on the receptor, allosteric modulators can alter orthosteric agonist efficacy or affinity, including endogenous opioid peptides, without altering their spatial and temporal release. Thus, the beneficial effects of the peptide ligands are promoted, and adverse effects can be reduced. Consequently, PAMs at DOR could be developed as drugs to treat depression. A previous high-throughput screening effort identified a series of xanthene-diones as DOR positive allosteric modulators, exemplified by BMS-986187 (1). However, BMS-986187 is also active as a positive allosteric modulator at MOR with lower activity. The lack of selectivity of BMS-986187 can be problematic by promoting the adverse effects of MOR agonists. Additionally, BMS-986187 exhibits a poor pharmacokinetic profile that hinders its druggability. The work outlined in this dissertation describes a structure-activity study of derivatives of BMS-986187 to further understand the DOR allosteric binding site and improve the potency and selectivity of BMS-986187. Due to the size, flexibility, and greasiness of the allosteric site, we could not optimize the potency of xanthene-dione series at DOR. However, although DOR and MOR share similarities at their allosteric binding sites I observed differences and have successfully optimized the selectivity of xanthen-dione series for DOR over MOR. By introducing additional conformation restriction and potential steric clashes by synthesizing compounds CCG363081 and CCG362904, the selectivity was improved by more than 1,000-fold while maintaining DOR potency (EC50 = 0.09 μM). As the xanthene-dione series shows impressive in vitro pharmacological activities, I next attempted to optimize its drug-like characteristics. I first tried improving the solubility profile to reduce its lipophilicity. However, due to the lipophilic nature of the proposed binding site, most of the analogs with exposed electronic effects completely lost DOR activity. Therefore, I shielded the substrates’ electronic effects through steric and conformational restriction. Although some loss in potency on DOR was observed, I was able to improve the solubility profile with analogs, CCG369831 and CCG363177. Additionally, I tried optimizing the metabolic stability of the xanthene-dione series to further improve its druggability. Metabolic soft spots of xanthene series were blocked. However, most of the attempts failed except for the incorporation of halogens. I demonstrated an improvement in metabolic stability profile with CCG366046 without losing potency at DOR and selectivity over MOR. To date, I have successfully optimized both the selectivity and metabolic stability of the xanthene series with CCG366046.