Role of spacer and address components in peptidomimetic .delta.-opioid receptor antagonists related to naltrindole

Abstract

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 delta opioid receptor antagonist activity. The benzofuran (NTB), quinoxaline, and quinoline analogues (2, 3, and 4, respectively) were delta-selective opioid antagonists in vitro and bound selectively to delta receptors. The tetrahydroindole derivative 5, while delta-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 delta address moiety. Moreover, the lower delta 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 delta address subsite that may accommodate the benzene moiety of NTI or the Phe4 phenyl group of leucine enkephalin. The considerably lower delta 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.

Blockade of δ-Opioid Receptors Prevents Morphine-Induced Place Preference in Mice

“…In the present study, the morphine (5 mg/kg)-induced place preference was completely prevented in ddY mice by all of the highly selective non-peptide 3-opioid recep tor antagonists tested, including NTI (24, 25) for d-, BNTX (26) for 61 and NTB (27) for o2-opioid receptors. By themselves, these o-opioid receptor antagonists, NTI (0.5 and 1 mg/kg), BNTX (0.35 and 0.7 mg/kg) and NTB (0.1 and 0.5 mg/kg), induced neither place preference nor place aversion.…”

Differential Effects of CB1 and Opioid Agonists on Two Populations of Adult Rat Dorsal Root Ganglion Neurons

“…Evidence for involvement of MORs includes blockade of the effect of morphine by CTAP at a concentration that selectively inhibits MORs (Bonner et al, 1997) and blockade by naltrindole at a concentration that blocks MORs and DORs (Portoghese et al, 1991;Raynor et al, 1994). Furthermore, DAMGO mimicked the effect of morphine at a concentration that selectively binds receptors (Erspamer et al, 1989).…”

Involvement of δ-opioid receptors in the effects of morphine on locomotor activity and the mesolimbic dopaminergic system in mice

“…A series of highly selective, non-peptide 6-opioid receptor antagonists, such as naltrindole (NTI) and naltriben (NTB), a benzofuran derivative of NTI, have recently been synthesized (Portoghese et al 1988(Portoghese et al , 1990(Portoghese et al , 1991. Therefore, we have investigated the role of the 6-opioid receptors in morphine-induced antinociception, hyperlocomotion and dopamine (DA) metabolism elevations in the limbic forebrain using NTI and NTB in mice.…”