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

Increasing the molecular rigidity of bioactive compounds by intramolecular hydrogen bonds (IMHB) may affect both pharmacodynamics (PD) and pharmacokinetics (PK) by an increase in molecular recognition, lipophilicity and membrane permeability. Recently, in our study on opioids lipophilicity, we suggested two types of IMHBs, i.e., O–H⋯N and N⁺-H^…O, which may exist in 14-oxymorphinan structures and may explain some trends and even apparent anomalies in their pharmacologically relevant molecular properties. In the present study we show, both experimentally and computationally, that these IMHBs indeed exist in the three FDA-approved opioid antagonists, Naloxone, Naltrexone and Nalmefene, as well as in their 3-O- and 14-O-methylated derivatives. Since the charged form of these morphinans is the biologically active species, we propose that the charge-assisted IMHB (CAHB) N⁺-H^…O, which is herein studied for the first time, plays an important role in the bioactivity of this subfamily of opioids.