Tolvaptan-Type Vasopressin Receptor Ligands: Important Role of Axial Chirality in the Active Form

The anti and syn isomers of tolvaptan-type
compounds, N-benzoyl-5-hydroxy-1-benzazepines (5a–c), were prepared in a stereocontrolled
manner by biasing the conformation with a methyl group at C9 and C6,
respectively, and the enantiomeric forms were separated. Examination
of the affinity at the human vasopressin receptors revealed that the
axial chirality (aS) plays a more important role
than the central chirality at C5 in receptor recognition, and the
most preferable form was shown to be (E,aS,5S).