Quantum chemical studies of N-substituent variation in the oxymorphone series of opiate narcotics.
Quantum chemical calculations were performed on six 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 method. The object of the study was to identify conformational features of the N-substituents 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 two. Direct effects of the C14-OH group on conformations of N-substituents also could not account for their relative agonist/antagonist potencies. Consistent with a previous hypothesis, 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.
D000701:Analgesics, Opioid; D000818:Animals; D004091:Hydromorphone / Q000031:analogs & derivatives*; D066298:In Vitro Techniques; D051379:Mice; D008968:Molecular Conformation; D010111:Oxymorphone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D011789:Quantum Theory; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine; D013816:Thermodynamics
D000701:Analgesics, Opioid; D010111:Oxymorphone; D004091:Hydromorphone