ELECTROPHILIC N-BENZYLNALTRINDOLES AS DELTA-OPIOID RECEPTOR-SELECTIVEANTAGONISTS

The N-benzyl group of N-benzylnaltrindole (1, BNTI), a potent and sele ctive delta(2) opioid receptor antagonist, was employed as a scaffold to hold electrophilic moieties (isothiocyanate and haloacetamide) in a n effort to obtain selective affinity labels (2-4 and 8-11). The corre sponding acetamide derivatives (5-7) also were synthesized to serve as nonelectrophilic controls. The o- and p-isothiocyanates (2 and 4) and the haloamides (8-11) were selective delta opioid receptor antagonist s in the mouse vas deferens (MVD) preparations, while the meta isomer 3 was a delta-selective full agonist (IC50 = 5 nM). The fact that the effect of 2 and 4 was found to increase as a function of time in MVD s uggests a covalent mechanism for the wash resistant component. The m-i sothiocyanate 3 was found to be a delta-selective and irreversible ago nist in the MVD, and it is suggested that it may be covalently binding to an agonist recognition site. In the mouse abdominal stretch antino ciceptive assay, compounds 2-4 and 9 were delta-selective antagonists but exhibited delta(2)/delta(1) selectivity ratios lower than that of BNTI.