Structural determinants of opioid activity in the orvinols and related structures: Ethers of orvinol and isoorvinol

A series of ethers of orvinol and isoorvinol has been prepared and evaluate d in opioid receptor binding and in vitro functional assays. The most strik ing finding was the very large difference in kappa-opioid receptor activity between the diastereomeric ethyl ethers: 46-fold in binding, 150-fold in G PI, and 900-fold in the [S-35]GTP gamma S assay in favor of the (R)-diaster eomer, Additionally in the (R)-series there was a 700-fold increase in kapp a-agonist potency in the [S-35]GTP gamma S assay when Oft was replaced by O Bn. The data can be explained in a triple binding site model: an II-bonding site, a lipophilic site, and an inhibitory site with which the 20-Me group in the (S)-ethers may interact. It appears that kappa-agonist binding of t he orvinols avoids the inhibitory site in the intramolecular H-bonded confo rmation.