Role of Spacer and Address Components in Peptidomimetic δ Opioid Receptor Antagonists Related to Naltrindole

A series of heterocyclic analogues 2-5 related to naltrindole (1) (NTI) and 6-arylnaltrexone derivatives 6-8 were synthesized in order to determine the role of the spacer and the address moieties in conferring i opioid receptor antagonist activity. The benzofuran (NTB), quinoxaline, and quinoline analogues (2, 3, and 4, respectively) were δ-selective opioid antagonists in vitro and bound selectively to δ receptors. The tetrahydroindole derivative 5, while δ-selective, was considerably less potent than its indole analogue 13. The data for 2-4 indicate that heterocycles other than pyrrole can serve as a spacer for the δ address moiety. Moreover, the lower δ antagonist potency of 5 illustrates the importance of the aromatic address component. Molecular dynamics simulations of enkephalin using a zipper binding model are consistent with a i address subsite that may accommodate the benzene moiety of NTI or the Phe⁴ phenyl group of leucine enkephalin. The considerably lower & opioid receptor antagonist potencies of the 6-aryl derivatives 6-8 are consistent with the conformational mobility of the aryl group and its location in the molecule.