Conjugate addition ligands of opioid antagonists. Methacrylate esters and ethers of 6α- and 6β-naltrexol

• Published in: Journal of medicinal chemistry Vol. 33; no. 2; pp. 737 - 741
• Main Authors: OLSEN, L. D, KLEIN, P, NELSON, W. L, YI-HE YAO, SIMON, E. J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.02.1990
• Subjects: 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; Pentacyclic compound; Opiate receptor; Diol; Lactone; Agonist antagonist; In vitro; Biological activity; Monocyclic compound; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00164a043

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.