Intramolecular hydrogen-bonding motifs in the 14-oxymorphinan opioids: An experimental and computational study

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Computational Chemistry

Background:

• Intramolecular hydrogen bonds (IMHBs) can influence the pharmacodynamics (PD) and pharmacokinetics (PK) of bioactive compounds.
• Two types of IMHBs, O-H⋯N and N⁺-H^…O, were previously hypothesized in 14-oxymorphinan structures.
• These IMHBs may explain observed trends and anomalies in opioid molecular properties.

Purpose of the Study:

• To experimentally and computationally confirm the existence of IMHBs in FDA-approved opioid antagonists.
• To investigate the role of charge-assisted intramolecular hydrogen bonds (CAHBs) in opioid bioactivity.

Main Methods:

• Experimental validation of IMHBs.
• Computational modeling and analysis.
• Study of Naloxone, Naltrexone, Nalmefene, and their methylated derivatives.

Main Results:

• Confirmed the presence of O-H⋯N and N⁺-H^…O IMHBs in Naloxone, Naltrexone, and Nalmefene.
• Demonstrated the existence of these IMHBs in their 3-O- and 14-O-methylated derivatives.
• Identified and studied the charge-assisted IMHB (CAHB) N⁺-H^…O for the first time.

Conclusions:

• IMHBs, particularly CAHBs, are present in key opioid antagonists.
• The N⁺-H^…O CAHB is proposed to play a significant role in the bioactivity of this opioid subfamily.
• Findings contribute to understanding opioid structure-activity relationships.