Nonequilibrium opioid antagonist activity of 6,14-dideoxynaltrexone derivatives

Abstract

A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3-5 of the series possessed irreversible antagonist activity profiles similar to those previously reported for the 14-hydroxy analogues. In contrast, the 14-deoxy-beta-funaltrexamine (14-deoxy-beta-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of beta-FNA. It was concluded that the 14-hydroxy group is not essential for irreversible blockage when the electrophile is capable of reacting with a broad spectrum of nucleophiles. However, with a highly selective electrophile such as the fumarate group, the 14-hydroxy function appears to play a role in aligning the molecule to optimize attack by a receptor-based nucleophile.

Synthesis and immunological effects of heroin vaccines

“…The configuration of the C6 side chain in 13a was suggested by NMR (the coupling constant J 5,6 in a compound with a C-6α-orientated side chain is smaller than that in a compound with a C-6β-orientated side chain 28 ). It was verified by X-ray crystallographic analysis ( Fig 3 ).…”

“…Complete information on data collection and refinement is available in the supplemental material. (4S,4aR,7S,7aR,12bR)-11-Chloro-3-methyl-2,3,4,4a,5,6,7,7aoctahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7amine (28). With stirring at room temperature, 3-deoxy-6amino-dihydromorphine (27, 520 mg 1.93 mmol), and N-chlorosuccinimide (514 mg, 3.85 mmol) were added to 0.1 N H 2 SO 4 (40 mL), and the mixture was heated at 90 °C for 3 h. After cooling to room temperature, NaOH (300 mg, 7.5 mmol) was added to the reaction mixture.…”