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 function al assays. Comparison of the ethyl ethers 4b and 5b with the parent alcohol s 4a and 5a, respectively, in both the (5'R) (= 5'beta) and (5'S) (= 5'alph a) 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 [S-35]GT P gamma S assay, the 5'beta-ethyl ether 4b had 80-fold greater kappa-agonis t potency than its epimer 5b. Increasing the size of the 5'beta-OR group ha s a major effect on mu-agonist efficacy and potency, a more modest effect o n delta-efficacy, and no effect on kappa-activity. These data show that mu- and delta-agonist efficacy is favoured by lipophilic binding in the area o ccupied by the Bu-t in the lowest-energy conformation of buprenorphine, and that kappa-agonist binding may involve interaction with an H-bond-donor gr oup in that region.