Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone

Very high affinity for opioid receptors (e.g., Ki = 0.052 nM for μ) has been observed in the rationally designed naltrexone analogue 5. SAR and physical data supports the hypothesis that the 4-OH group of 5 stabilizes the 3-carboxamido group in the putative bioactive conformation.

Graphical abstractNovel analogue 5 of naltrexone displays very high affinity for opioid receptors with Ki values of 0.052 nM, 2.6 nM and 0.23 nM for μ, δ and κ, respectively.Figure optionsDownload full-size imageDownload as PowerPoint slide