TY - JOUR
T1 - Structural determinants of opioid activity in the orvinols and related structures. Ethers of 7,8-cyclopenta-fused analogs of buprenorphine
AU - Coop, Andrew
AU - Berzetei-Gurske, Ilona
AU - Burnside, Jackie
AU - Toll, Lawrence
AU - Traynor, John R.
AU - Husbands, Stephen M.
AU - Lewis, John W.
PY - 2000/4/12
Y1 - 2000/4/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0034101429&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1522-2675(20000412)83:4<687::AID-HLCA687>3.0.CO;2-W
DO - 10.1002/(SICI)1522-2675(20000412)83:4<687::AID-HLCA687>3.0.CO;2-W
M3 - Article
AN - SCOPUS:0034101429
SN - 0018-019X
VL - 83
SP - 687
EP - 693
JO - Helvetica Chimica Acta
JF - Helvetica Chimica Acta
IS - 4
ER -