Syntheses of novel high affinity ligands for opioid receptors

A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring ‘open’ derivatives display very high affinity for μ and κ receptors and much less affinity for δ. The observation that these target compounds have much higher receptor affinity than the corresponding ring ‘closed’ carboxamides significantly strengthens our underlying pharmacophore hypothesis concerning the bioactive conformation of the carboxamide group.

High binding affinity [Ki values (μ) = 0.072–1.3 nM] to opioid receptors is seen in a novel series of 3-desoxy-3-carboxamido-4-hydroxymorphinans where the carboxamide group is stabilized in the putative bioactive conformation.Figure optionsDownload as PowerPoint slide