4'-Arylpyrrolomorphinans: effect of a pyrrolo-N-benzyl substituent in enhancing delta-opioid antagonist activity.

A new method for the preparation of N-benzylpyrrolomorphinans has been developed. Thus Michael reaction of the benzylimines of oxycodones and oxymorphones with nitrostyrenes gave a series of 4'-aryl-N-benzylpyrrolomorphinans. These were selective delta antagonists of much higher in vitro potency (with 5a having K(e) delta = <1 nM) than their binding affinities predicted. In mice in vivo assays 5a showed good delta antagonist activity in the anti-writhing analgesic assay and also inhibited delta agonist-induced convulsant activity.