Discovery and synthesis of a new class of opioid ligand having a 3-azabicyclo[3.1.0]hexane core. An example of a ‘magic methyl’ giving a 35-fold improvement in binding

In looking for a novel achiral μ opioid receptor antagonist for the treatment of pruritus, we designed and synthesised azabicyclo[3.1.0]hexane compounds as a new class of opioid ligand. During optimisation, an addition of a single methyl resulted in a 35-fold improvement in binding. An early example from the series had excellent μ opioid receptor antagonist antagonist activity and was very effective in an in vivo pruritus study.

Graphical abstractThe synthesis and biological evaluation of 3-azabicyclo[3.1.0]hexane mu opioid receptor antagonists 2 and 3 are reported. The significant potency enhancement made by a single methyl substituent is discussed.Figure optionsDownload full-size imageDownload as PowerPoint slide