Opioid receptor interactions and conformations of the 6 alpha and 6 beta epimers of oxymorphamine. Solid-state conformation of 6 alpha-oxymorphamine.
The affinities of the oxymorphamine epimers for mu and delta opioid receptors were determined in vitro. The 6 alpha and 6 beta epimers are potent mu-selective ligands with similar receptor-binding profiles. The relatively undramatic effect of C-6 chirality on receptor interactions is intriguing in view of the recently demonstrated profound influence of C-6 chirality on ring-C solution conformations (ring C is a chair conformer in the beta epimer but adopts a twist-boat conformation in the alpha epimer) and prompted the determination of the crystal structure of alpha-oxymorphamine. The crystal structure showed that ring C in this epimer also adopts a twist-boat conformation in the solid state. Molecular modeling of the oxymorphamines in the preferred ring-C conformations (alpha = boat, beta = chair) demonstrated that the 6-amino groups project to spatial loci significantly more proximal (0.35 A) than would be the case (2.2 A) if both epimers adopted chair conformations for ring C. Consequently, although the epimeric oxymorphamines differ in ring-C conformation, the principle potential heteroatomic binding sites in each epimer are oriented similarly, which may be partly responsible for the lack of dramatic differences in receptor binding profiles.
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D000818:Animals; D001921:Brain / Q000378:metabolism; D004091:Hydromorphone / Q000031:analogs & derivatives*; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010111:Oxymorphone / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011957:Receptors, Opioid; C036406:oxymorphamine; D010111:Oxymorphone; D004091:Hydromorphone