title: Electrophilic alpha-methylene-gamma-lactone and isothiocyanate opioid ligands related to etorphine.
abstract: Isothiocyanate and alpha-methylene-gamma-lactone analogues of 6,14-endo-ethenotetrahydrothebaine and -oripavine were prepared with the electrophilic groups being located at C-19 in the C-7 alpha-side chain. Isothiocyanates were prepared in the N-Me and N-CPM (N-cyclopropylmethyl) series, both as the phenols and 3-O-methyl ethers from the diastereomeric amines formed from reductive amination of thevinone (2) and N-(cyclopropylmethyl)northevinone (13). Although addition of the organozinc reagent from methyl alpha-bromomethacrylate to 25 failed, addition to 3-O-protected aldehydes 27 and 35 produced, after subsequent deprotection, alpha-methylene-gamma-lactones 29 and 37, respectively. In the opioid receptor displacement assays against [3H]bremazocine as the radiolabeled ligand, the phenolic compounds were most potent with N-CPM isothiocyanates 20 and 21 showing IC50s of 0.32 and 0.76 nM, respectively, and N-CPM alpha-methylene-gamma-lactone 37 having an IC50 = 1.0 nM. Compound 37 showed irreversible effects in the binding assay which were mu-selective, as demonstrated by analogous experiments using [3H]DAGO, and naloxone was found to protect against the irreversible effects. This observation suggests that a receptor-bound nucleophile is located at a position where it can readily reach the alpha-methylene group of lactone 37.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: P
authors.initials: P
authors.lastname: Klein
authors.forename: W L
authors.initials: WL
authors.lastname: Nelson
authors.forename: Y H
authors.initials: YH
authors.lastname: Yao
authors.forename: E J
authors.initials: EJ
authors.lastname: Simon
mesh_terms: D055598:Chemical Phenomena; D002621:Chemistry; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D005048:Etorphine / Q000031:analogs & derivatives* / Q000378:metabolism; D017879:Isothiocyanates; D007783:Lactones; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009019:Morphinans; D009270:Naloxone / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D017450:Receptors, Opioid, mu; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D013797:Thebaine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism; D013861:Thiocyanates
chemical_list: D004745:Enkephalins; D017879:Isothiocyanates; D007783:Lactones; D008024:Ligands; D009019:Morphinans; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D013861:Thiocyanates; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C065063:N-(cyclopropylmethyl)-6,14-endo-etheno-7-(3-carboxy-3-n-butenyl)tetrahydronororipavine gamma-lactone; D013797:Thebaine; C037152:isothiocyanic acid; D009270:Naloxone; D005048:Etorphine