Investigation of Phenolic Bioisosterism in Opiates: 3-Sulfonamido Analogues of Naltrexone and Oxymorphone

Abstract
The phenolic hydroxy group of opiate-derived ligands is of known importance for biological activity. On the basis of its putative role as a hydrogen-bonding donor in the interaction with opioid receptors, it was replaced with a sulfonamide group because of their similar pKa values. The first thebaine-derived 3-amino (8a, 8b) and subsequent sulfonamide analogues (10a, 10b) were synthesized from naltrexone (1a) and oxymorphone (1b) in a linear nine-step synthesis. The sulfonamides were tested in vitro and found inactive.