Structural determinants of opioid activity in the orvinols and related structures: Ethers of orvinol and isoorvinol

Andrew Coop; Claire L. Norton; Ilona Berzetei-Gurske; Jackie Burnside; Lawrence Toll; Stephen M. Husbands; John W. Lewis

doi:10.1021/jm990951r

Structural determinants of opioid activity in the orvinols and related structures: Ethers of orvinol and isoorvinol

Andrew Coop, Claire L. Norton, Ilona Berzetei-Gurske, Jackie Burnside, Lawrence Toll, Stephen M. Husbands, John W. Lewis

Research output: Contribution to journal › Article › peer-review

Abstract

A series of ethers of orvinol and isoorvinol has been prepared and evaluated in opioid receptor binding and in vitro functional assays. The most striking finding was the very large difference in K-opioid receptor activity between the diastereomeric ethyl ethers: 46-fold in binding, 150-fold in GPI, and 900-fold in the [³⁵S]GTPγS assay in favor of the (R)-diastereomer. Additionally in the (R)-series there was a 700-fold increase in K-agonist potency in the [₃₅S]GTPγS assay when OEt was replaced by OBn. The data can be explained in a triple binding site model: an H-bonding site, a lipophilic site, and an inhibitory site with which the 20-Me group in the (S)-ethers may interact. It appears that K-agonist binding of the orvinols avoids the inhibitory site in the intramolecular H-bonded conformation.

Original language	English
Pages (from-to)	1852-1857
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	43
Issue number	9
DOIs	https://doi.org/10.1021/jm990951r
Publication status	Published - 1 May 2000

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Structural determinants of opioid activity in the orvinols and related structures: Ethers of orvinol and isoorvinol",

abstract = "A series of ethers of orvinol and isoorvinol has been prepared and evaluated in opioid receptor binding and in vitro functional assays. The most striking finding was the very large difference in K-opioid receptor activity between the diastereomeric ethyl ethers: 46-fold in binding, 150-fold in GPI, and 900-fold in the [35S]GTPγS assay in favor of the (R)-diastereomer. Additionally in the (R)-series there was a 700-fold increase in K-agonist potency in the [35S]GTPγS assay when OEt was replaced by OBn. The data can be explained in a triple binding site model: an H-bonding site, a lipophilic site, and an inhibitory site with which the 20-Me group in the (S)-ethers may interact. It appears that K-agonist binding of the orvinols avoids the inhibitory site in the intramolecular H-bonded conformation.",

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T1 - Structural determinants of opioid activity in the orvinols and related structures

T2 - Ethers of orvinol and isoorvinol

AU - Coop, Andrew

AU - Norton, Claire L.

AU - Berzetei-Gurske, Ilona

AU - Burnside, Jackie

AU - Toll, Lawrence

AU - Husbands, Stephen M.

AU - Lewis, John W.

PY - 2000/5/1

Y1 - 2000/5/1

N2 - A series of ethers of orvinol and isoorvinol has been prepared and evaluated in opioid receptor binding and in vitro functional assays. The most striking finding was the very large difference in K-opioid receptor activity between the diastereomeric ethyl ethers: 46-fold in binding, 150-fold in GPI, and 900-fold in the [35S]GTPγS assay in favor of the (R)-diastereomer. Additionally in the (R)-series there was a 700-fold increase in K-agonist potency in the [35S]GTPγS assay when OEt was replaced by OBn. The data can be explained in a triple binding site model: an H-bonding site, a lipophilic site, and an inhibitory site with which the 20-Me group in the (S)-ethers may interact. It appears that K-agonist binding of the orvinols avoids the inhibitory site in the intramolecular H-bonded conformation.

AB - A series of ethers of orvinol and isoorvinol has been prepared and evaluated in opioid receptor binding and in vitro functional assays. The most striking finding was the very large difference in K-opioid receptor activity between the diastereomeric ethyl ethers: 46-fold in binding, 150-fold in GPI, and 900-fold in the [35S]GTPγS assay in favor of the (R)-diastereomer. Additionally in the (R)-series there was a 700-fold increase in K-agonist potency in the [35S]GTPγS assay when OEt was replaced by OBn. The data can be explained in a triple binding site model: an H-bonding site, a lipophilic site, and an inhibitory site with which the 20-Me group in the (S)-ethers may interact. It appears that K-agonist binding of the orvinols avoids the inhibitory site in the intramolecular H-bonded conformation.

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Structural determinants of opioid activity in the orvinols and related structures: Ethers of orvinol and isoorvinol

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