ELECTROPHILIC ALPHA-METHYLENE-GAMMA-LACTONE AND ISOTHIOCYANATE OPIOID LIGANDS RELATED TO ETORPHINE

Isothiocyanate and a-methylene-7-lactone analogues of 6,14-endo-ethenotetrahydrothebaine and -oripavine were prepared with the electrophilic groups being located at C-19 in the C-7a-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 a-bromomethacrylate to 25 failed, addition to 3-O-protected aldehydes 27 and 35 produced, after subsequent deprotection, α-methylene-ϒ-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 α-methylene-ϒ-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 [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 a-methylene group of lactone 37. A series of potential prodrugs of 2-amino-3-benzoylbenzeneacetic acid (amfenac) and 2-amino-3-(4-chlorobenzoyl)benzeneacetic acid were synthesized and evaluated for their cyclooxygenase inhibiting properties, antiinflammatory potency, and gastrointestinal irritation liability. One compound, 2-amino-3-(4-chlorobenzoyl)-benzeneacetamide, possessed a therapeutic index 1 order of magnitude greater than that of indomethacin. © 1990, American Chemical Society. All rights reserved.