Structural determinants of opioid activity in the orvinols and related structures. Ethers of 7,8-cyclopenta-fused analogs of buprenorphine

A series of ethers of 7,8-cyclopenta-fused analogs of the orvinols related to buprenorphine were prepared and evaluated in opioid-binding and functional assays. Comparison of the ethyl ethers 4b and 5b with the parent alcohols 4a and 5a, respectively, in both the (5'R) (= 5'β) and (5'S) (= 5'α) series, shows that the 20-OH group in the orvinols (corresponding to 5'-OH of 4 and 5) is not crucial for opioid activity, although in the [³⁵S]GTPγS assay, the 5'β-ethyl ether 4b had 80-fold greater κ-agonist potency than its epimer 5b. Increasing the size of the 5'β-OR group has a major effect on μ-agonist efficacy and potency, a more modest effect on δ- efficacy, and no effect on κ-activity. These data show that μ- and δ- agonist efficacy is favoured by lipophilic binding in the area occupied by the 'Bu in the lowest-energy conformation of buprenorphine, and that κ- agonist binding may involve interaction with an H-bond-donor group in that region.