Electrophilic opioid ligands. Oxygen tethered alpha-methylene-gamma-lactone, acrylate, isothiocyanate, and epoxide derivatives of 6 beta-naltrexol.
Basic Information
ID: ALA1126090
Journal: J Med Chem
Title: Electrophilic opioid ligands. Oxygen tethered alpha-methylene-gamma-lactone, acrylate, isothiocyanate, and epoxide derivatives of 6 beta-naltrexol.
Authors: Dasher WE, Klein P, Nelson WL.
Abstract: O6-Ether derivatives of 6 beta-naltrexol in which the ether substituent includes various electrophilic groups have been synthesized in an effort to examine structure-activity requirements at the 6 beta-substituent for receptor affinity and irreversibility of binding in opioid receptor preparations. A series of tethered 6 beta-ethers having terminal epoxides, alpha-methylene-gamma-lactones, and an isothiocyanate group were prepared. The stereochemistry of the alpha-methylene-gamma-lactones was established by convergent synthesis of their reduction products from epoxides of known absolute stereochemistry. In general, the tested compounds showed comparable affinity and selectivity for the receptor subtypes. All were found with high affinity for mu-sites. The terminal epoxide ether diastereomers 8 and 9 were not bound irreversibly in the assay for total opioid receptors. The alpha-methylene-gamma-lactone diastereomers 10 and 11, and their O14-acetyl precursors 20 and 21, respectively, varied in their irreversible effects, but where noted these effects were mu-site selective. Methacrylate ether 7 and isothiocyanate ether 12 were bound irreversibly at both mu- and delta-sites.
CiteXplore: 1320121
DOI: 10.1021/jm00091a005
Patent ID: ┄