Diastereomeric 6-desoxy-6-spiro-.alpha.-methylene-.gamma.-butyrolactone derivatives of naltrexone and oxymorphone. Selective irreversible inhibition of naltrexone binding in an opioid receptor preparation by a conformationally restricted Michael acceptor ligand

• Published in: Journal of medicinal chemistry Vol. 27; no. 12; pp. 1718 - 1723
• Main Authors: Koolpe, Gary A, Nelson, Wendel L, Gioannini, T. L, Angel, Lloyd, Simon, Eric J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.12.1984
• Subjects: Animals; Brain - metabolism; Cell Membrane - metabolism; Chemistry; Chromatography, Thin Layer; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Hydromorphone - analogs & derivatives; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Molecular Conformation; Naloxone - analogs & derivatives; Naltrexone - analogs & derivatives; Naltrexone - antagonists & inhibitors; Naltrexone - chemical synthesis; Naltrexone - metabolism; Naltrexone - pharmacology; Narcotic Antagonists - chemical synthesis; Optical Rotation; Organic chemistry; Oxymorphone - analogs & derivatives; Oxymorphone - chemical synthesis; Oxymorphone - pharmacology; Preparations and properties; Rats; Rats, Inbred Strains; Receptors, Opioid - drug effects; Receptors, Opioid - metabolism; Structure-Activity Relationship; Pentacyclic compound; Opiate receptor; Five membered ring; Lactone; Oxygen heterocycle; Biological activity; Diastereomer; Spiran; Conformation; Oxygen nitrogen heterocycle
• DOI: 10.1021/jm00378a032
• ISSN: 0022-2623

The diastereomeric 6-desoxy-6-spiro-alpha-methylene-gamma-butyrolactone derivatives of naltrexone (4a and 5a) and of oxymorphone (4b and 5b) were prepared from their parent ketones. Diastereomers 4a and 4b were obtained from the 3,14-diacetate derivatives of naltrexone (6a) and oxymorphone (6b) by reaction with the Reformatsky reagent prepared from methyl alpha-(bromomethyl)acrylate. Deacetylation with methanol completed the synthesis. Diastereomers 5a and 5b were obtained from oxiranes 8a and 8b, respectively. The oxiranes were allowed to react with the sodium salt of ethyl acetoacetate, followed by methenation and deprotection to complete the synthesis of 5a and 5b, respectively. Compound 5a was the most potent agent tested in competition against [3H]naltrexone in the opioid radioreceptor assay. At a concentration of 5 nM this compound produced a 50% inhibition of binding. The majority of this inhibition (30%) was irreversible, i.e., it remained even after extensive washing of the membrane preparation in the presence and absence of Na+. Naloxone protected against this irreversible effect. The data suggest a receptor nucleophile, perhaps a sulfhydryl group, is located where it can add to the alpha, beta-unsaturated carbonyl system of 5a.