Electrophilic N-Benzylnaltrindoles as δ Opioid Receptor-Selective Antagonists

The N-benzyl group of N-benzylnaltrindole (1, BNTI), a potent and selective δ₂ opioid receptor antagonist, was employed as a scaffold to hold electrophilic moieties (isothiocyanate and haloacetamide) in an effort to obtain selective affinity labels (2-4 and 8-11). The corresponding 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 δ opioid receptor antagonists in the mouse vas deferens (MVD) preparations, while the meta isomer 3 was a δ-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 suggests a covalent mechanism for the wash resistant component. The m-isothiocyanate 3 was found to be a ó-selective and irreversible agonist in the MVD, and it is suggested that it may be covalently binding to an agonist recognition site. In the mouse abdominal stretch antinociceptive assay, compounds 2-4 and 9 were δ-selective antagonists but exhibited δ₂/δ₁ selectivity ratios lower than that of BNTI.