Structural Determinants of Opioid Activity in Derivatives of 14-Aminomorphinones: Effects of Changes to the Chain Linking the C14-Amino Group to the Aryl Ring

摘要

The 14-aminodihydromorphinone and codeinone series of opioid ligands have produced a number of ligands of substantial interest. In order to investigate the importance of the 14-substituent a series of analogues in which the side chain length is varied and the amide and alkene functions are reduced have been prepared. Binding affinity, particularly at the mu opioid receptor (MOR), was largely determined by the aromatic group of the side chain. In the [³⁵S]GTPγS functional assay, the ligands having a three carbon side chain were more potent antagonists than their longer chain counterparts, whilst shorter, 2 carbon chain analogues were of higher MOR efficacy, an effect that was confirmed in vivo. Wash-resistant binding was observed within this series and appeared to be unrelated to side chain length.