How Subtle Molecular Differences in the Morphinan Opioid Antagonists Affect Their Physicochemical and In Vitro ADME Properties

Abstract Naloxone, naltrexone and nalmefene are closely related morphinan antagonists with comparable affinities to the μ-opioid receptor (MOR) but markedly different pharmacokinetics (PK) and metabolic fate. In this study, we evaluated their pharmacologically-relevant molecular/physicochemical properties, PAMPA-BBB (Parallel Artificial Membrane Permeability Assay for the Blood-Brain Barrier) permeability and in vitro metabolic stability to determine how subtle structural differences influence ADME-relevant properties. Moreover, the pharmacologically-relevant properties of these three antagonists were compared with those of the best-known synthetic opioid agonist, fentanyl. We found that the methyl-cyclopropyl versus allyl head group, as well as the C6-carbonyl versus C6-ethenyl group, dramatically influence all the above-mentioned properties and help explain the in vivo observed differences between these antagonists. These results may support the rational design of new and improved opioid antagonists with optimized PK properties.