Discovery of MOR Selective, Reversible Opioid Antagonists for Potential Use in Treatment of Drug Dependence

Abstract

Opioid dependence/addiction is a major public health problem that is associated with multiple health and social costs. Opioids were responsible for the majority of deaths resulting from a drug overdose in 2015 (63% of 52,404). The FDA has approved methadone and buprenorphine for long‐term agonist maintenance therapy. However, a large portion of patients relapse to heroin or illicit use of prescribed opioids. One approach to minimize drug‐induced relapse risk is switching patients to long‐term antagonist therapy after weaning off with an agonist. Naltrexone (NTX) is the only opioid antagonist that is approved for opioid dependence treatment. Nevertheless, NTX is associated with side effects including dysphoria and depression, which contribute to poor patient compliance. Some side effects of NTX could be due in part to its lack of selectivity, as NTX has moderate affinity for the kappa opioid receptors (KOR). Currently, there are no highly‐selective, reversible, non‐peptide μ opioid receptor (MOR) antagonists. Therefore, 18 novel indole‐substituted epoxymorphinan ligands were designed based on the message‐address concept and molecular modeling studies, and synthesized. These novel ligands were hypothesized to bind selectively to the MOR based on interaction with a key aromatic residue in extracellular loop 3 of the MOR (Trp318), such that the added indole substituent in the structure might favor interaction with the indole ring in Trp318 in MOR over KOR and delta opioid receptors (DOR). The purpose of this study was to identify potential MOR‐selective antagonists from this series of compounds using radioligand and [35S]GTPγS binding assays in Chinese Hamster Ovary cells that were stably expressing mouse opioid receptors of interest (MOR, KOR or DOR) and ICR male mouse thalamus. Results showed that all 18 compounds bind to the MOR with high affinity (Ki ≤1 nM) and exhibit a range of efficacies for MOR‐mediated G‐protein activation. Two compounds were discovered to possess most of the desired features. Both compounds have high MOR‐affinity (<1 nM), high MOR selectivity over DOR (>50‐fold) and moderate selectivity over KOR (~8‐fold,) as well as low efficacy to activate the MOR (<20% of the full MOR agonist, [D‐Ala2, N‐MePhe4, Gly‐ol]‐enkephalin (DAMGO)). They also competitively right‐shifted DAMGO‐concentration effect curves for G‐protein activation similarly to naltrexone, indicating they act as competitive MOR antagonists. Our results are encouraging to advance these two compounds for further in‐vitro and in‐vivo pharmacological characterization, and provide important pharmacological information to aid future ligand design.Support or Funding InformationNIH grant R01‐DA024022; Jazan UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.