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-β-funaltrexamine (14-deoxy-β-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of β-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.