Quantum chemical studies of N-substituent variation in the oxymorphone series of opiate narcotics

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Abstract
Quantum chemical calculations were performed on 6 N-derivatives of oxymorphone including N-methyl-(oxymorphone), N-allyl-(naloxone), N-dimethylallyl-(nalmexone), N-methylcyclopropyl-(naltrexone), N-methylcyclobutyl(nalbuphone) and N-phenethylnoroxymorphone using the PCILO [computer program] method. Conformational features of the N-substituents were identified which might be responsible for the intrinsic observed pharmacological properties of opiate agonism and antagonism. Both axial and equatorial N-substituent conformers were considered, as well as possible interactions of the C14-OH group with such substituents. Variations of agonist/antagonist potency ratios within this series could not be explained by differing relative energies of equatorial and axial conformations or by varying rates of interconversion between the 2. Direct effects of the C14-OH group on conformations of N-substituents also could not account for their relative agonist/antagonist potencies. The observed potencies and binding data could be explained most consistently by the availability of several low energy equatorial conformations of N-substituents and their interactions with the C14-OH group through a common anionic receptor site.