Conjugate addition ligands of opioid antagonists. Methacrylate esters and ethers of 6α- and 6β-naltrexol
Alpha- and beta-naltrexol derived esters 9 and 10 and ethers 11 and 12, each containing the alpha, beta-unsaturated ester functionality, were prepared as conformationally more flexible analogues of spiro-alpha-methylene-gamma-lactones 5 and 6. All were active in the opioid radioreceptor binding assa...
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Published in | Journal of medicinal chemistry Vol. 33; no. 2; pp. 737 - 741 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Washington, DC
American Chemical Society
01.02.1990
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Subjects | |
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Abstract | Alpha- and beta-naltrexol derived esters 9 and 10 and ethers 11 and 12, each containing the alpha, beta-unsaturated ester functionality, were prepared as conformationally more flexible analogues of spiro-alpha-methylene-gamma-lactones 5 and 6. All were active in the opioid radioreceptor binding assay against [3H]bremazocine and more active against [3H]DAGO, indicating mu-subtype selectivity, but only ether 12 showed significant irreversible activity. We conclude that small structural changes, made in very closely related electrophilic opioids, lead to changes in receptor binding. All four compounds were long-acting antagonists to morphine in mice, with ester 10 being approximately equipotent with naltrexone. |
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AbstractList | Alpha- and beta-naltrexol derived esters 9 and 10 and ethers 11 and 12, each containing the alpha, beta-unsaturated ester functionality, were prepared as conformationally more flexible analogues of spiro-alpha-methylene-gamma-lactones 5 and 6. All were active in the opioid radioreceptor binding assay against [3H]bremazocine and more active against [3H]DAGO, indicating mu-subtype selectivity, but only ether 12 showed significant irreversible activity. We conclude that small structural changes, made in very closely related electrophilic opioids, lead to changes in receptor binding. All four compounds were long-acting antagonists to morphine in mice, with ester 10 being approximately equipotent with naltrexone. |
Author | YI-HE YAO NELSON, W. L OLSEN, L. D SIMON, E. J KLEIN, P |
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Keywords | Pentacyclic compound Opiate receptor Diol Lactone Agonist antagonist In vitro Biological activity Monocyclic compound Oxygen nitrogen heterocycle |
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Snippet | Alpha- and beta-naltrexol derived esters 9 and 10 and ethers 11 and 12, each containing the alpha, beta-unsaturated ester functionality, were prepared as... |
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SubjectTerms | Animals Benzomorphans - metabolism Binding, Competitive Cattle Caudate Nucleus - metabolism Chemistry Enkephalin, Ala-MePhe-Gly Enkephalins - metabolism Esters Ethers Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms In Vitro Techniques Ligands Methacrylates Naltrexone - analogs & derivatives Naltrexone - chemical synthesis Naltrexone - metabolism Organic chemistry Preparations and properties Receptors, Opioid - drug effects Structure-Activity Relationship |
Title | Conjugate addition ligands of opioid antagonists. Methacrylate esters and ethers of 6α- and 6β-naltrexol |
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