Intramolecular hydrogen bonding and conformational studies of bridged thebaine and oripavine opiate narcotic agonists and antagonists.
A conformational study of a series of oripavine derivatives is reported using the PCILO semiempirical quantum mechanical method. Low-energy conformers of carbinol substituents on C7-C19-R1R2OH are found with and without intramolecular hydrogen bonding to the C6-OCH3 group. The relative energies of these conformers depend on the R1 and R2 groups and the diastereoisomerism of the alcohol. The results are consistent with available NMR and IR studies of intramolecular hydrogen bonding and with crystallographic data. The importance of interaction between specific conformations of C19 carbinols and a lipophilic receptor site is suggested. A hypothesis is formulated to explain observed differences in pharmacological activity between diastereoisomers at C19 in the oripavine series and also to explain how these diastereoisomers alter the established pattern of N-substituent effects on relative agonist/antagonist potency found in other rigid opiates. By contrast, conformational studies of the C19 optical isomers of the C7-C8 etheno form of buprenorphine lead to the prediction of greatly reduced intrinsic potency differences between C19 diastereoisomers for this compound and for buprenorphine itself.
D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D009292:Narcotic Antagonists; D009294:Narcotics; D011789:Quantum Theory; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013797:Thebaine / Q000031:analogs & derivatives*; D013816:Thermodynamics
D009292:Narcotic Antagonists; D009294:Narcotics; D013797:Thebaine