Conformational properties of α‐ and β‐azabicyclane opiates. The effect of conformation on pharmacological activity

Abstract

Abstract Conformational energy calculations using the MM 2 (molecular mechanics II) program are reported for diastereoisomeric α‐ and β‐azabicyclanes (3‐methyl‐9‐methoxy‐9‐phenyl‐3‐azabicyclo [3.3.1] nonanes) which are prototypical phenyl‐axial and phenyl‐equatorial opiates. After energy minimization, both compounds are found to prefer a chair–chair conformation of the piperidine and cyclohexane rings with two mirror image orientations of the phenyl and methoxyl groups. The calculations also indicate that the equilibrium conformations of the phenyl and methoxyl groups are very similar in the two diastereoisomers. A morphine‐like conformation of the phenyl group was found to be very unfavorable because of a high barrier to rotation of the phenyl group. This does not have an apparent effect on opiate agonist properties, but does result in a significant weakening of the antagonist activity of the N‐allyl derivative of α‐azabicyclane. This is discussed in terms of a model for phenyl‐axial and phenyl‐equatorial opiate substrates which accounts for both similarities and differences in their structure–activity relationships. A detailed comparison is also made between the computed structures and those observed by x‐ray crystallography with excellent agreement between the two.