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

Andrew Coop, Ilona Berzetei-Gurske, Jackie Burnside, Lawrence Toll, John R. Traynor, Stephen M. Husbands, John W. Lewis

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Abstract

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.

Original languageEnglish
Pages (from-to)687-693
Number of pages7
JournalHelvetica Chimica Acta
Volume83
Issue number4
DOIs
Publication statusPublished - 12 Apr 2000

ASJC Scopus subject areas

  • Catalysis
  • Biochemistry
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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