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Structural Determinants of Opioid Activity in the Orvinols and Related Structures. Ethers of 7,8‐Cyclopenta‐Fused Analogs of Buprenorphine
Author(s) -
Coop Andrew,
BerzeteiGurske Ilona,
Burnside Jackie,
Toll Lawrence,
Traynor John R.,
Husbands Stephen M.,
Lewis John W.
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(20000412)83:4<687::aid-hlca687>3.0.co;2-w
Subject(s) - chemistry , agonist , potency , epimer , buprenorphine , stereochemistry , partial agonist , opioid , intrinsic activity , biochemistry , receptor , in vitro
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 [ 35 S]GTP γ S 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 t 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.