O‐Silyl Codeine Analogues as Ligands for Opioid Receptors

A series of novel opioid derivatives were designed and synthesized. Further binding and functional studies demonstrated that all analogues act as antagonists of the μ‐opioid receptor (MOR). This study highlights that a chemical modification at position 6 in combination with substituents on the nitrogen of codeine can lead to increased activity at the MOR. In particular, the conversion of alcohol to silyl ether at position 6 of codeine and norcodeine using tert ‐butyldiphenylsilyl (TBDPS) group led to increased activity at the MOR. Furthermore, the introduction of a smaller silyl group such as tert ‐butyldimethylsilyl (TBDMS) at position 6 of norcodeine in combination with an N ‐substitution also led to increased MOR activity. These findings may serve as a promising lead for the development of chemical probes as well as for further investigation of ligand‐opioid interactions and non‐covalent codeine analogues for opioid receptors.