INTRA-MOLECULAR 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-OCH3group. The relative energies of these conformers depend on the R1and R2groups 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 C19carbinols and a lipophilic receptor site is suggested. A hypothesis is formulated to explain observed differences in pharmacological activity between diastereoisomers at C19in 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 C19optical isomers of the C7-C8etheno form of buprenorphine lead to the prediction of greatly reduced intrinsic potency differences between C19diastereoisomers for this compound and for buprenorphine itself. © 1979, American Chemical Society. All rights reserved.