127154-03-4Relevant articles and documents
Electrophilic α-Methylene-γ-lactone and Isothiocyanate Opioid Ligands Related to Etorphine
Klein, Peter,Nelson, Wendel L.,Yao, Yi-He,Simon, Eric J.
, p. 2286 - 2296 (2007/10/02)
Isothiocyanate and α-methylene-γ-lactone analogues of 6,14-endo-ethenotetrahydrothebaine and -oripavine were prepared with the electrophilic groups being located at C-19 in the C-7α-side chain.Isothiocyanates were prepared in the N-Me and N-CPM (N-cyclopropylmethyl) series, both as the phenols and 3-O-methyl esters from the diastereomeric amines formed from reductive amination of thevinone (2) and N-(cyclopropylmethyl)northevinone (13).Although addition of the organozinc reagent from methyl α-bromomethacrylate to 25 failed, addition to 3-O-protected aldehydes 27 and 35 produced, after subsequent deprotection, α-methylene-γ-lactones 29 and 37, respectively.In the opioid receptor displacement assays against 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 α-methylene-γ-lactone 37 having an IC50 = 1.0 nM.Compound 37 showed irreversible effects in the binding assay which were μ-selective, as demonstrated by analogous experiments using 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 α-methylene group of lactone 37.
