Nitro-benzylideneoxymorphone, a bifunctional mu and delta opioid receptor ligand with high mu opioid receptor efficacy

Introduction: There is a major societal need for analgesics with less tolerance, dependence, and abuse liability. Preclinical rodent studies suggest that bifunctional ligands both mu (MOPr) delta (DOPr) opioid peptide receptor activity may produce analgesia reduced tolerance other side effects. This study explores the structure-activity relationships (SAR) of our previously reported MOPr/DOPr lead, benzylideneoxymorphone (BOM) C7-methylene-substituted analogs. Methods: Analogs were synthesized tested in vitro binding efficacy. One compound, nitro-BOM (NBOM, 12) was evaluated antinociceptive effects warm water tail withdrawal assay C57BL/6 mice. Acute chronic antinociception determined, as toxicologic on administration. Molecular modeling experiments performed using Site Identification by Ligand Competitive Saturation (SILCS) method. Results: NBOM found to be potent MOPr agonist/DOPr partial agonist produces high-efficacy antinociception. Antinociceptive observed, weight loss; this toxicity only observed not BOM. Modeling supports hypothesis increased efficacy due substituted benzylidene ring occupying nonpolar region within state. Discussion: Though non-specific repeated administration, provides an important new tool understanding pharmacology.