Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series

Abstract

Given the mounting evidence for involvement of delta opioid receptors in the tolerance and physical dependence of mu opioid receptor agonists, we have investigated the possible physical interaction between mu and delta opioid receptors by using bivalent ligands. Based on reports of suppression of antinociceptive tolerance by the delta antagonist naltrindole (NTI), bivalent ligands [mu-delta agonist-antagonist (MDAN) series] that contain different length spacers, and pharmacophores derived from NTI and the mu agonist oxymorphone, have been synthesized and evaluated by intracerebroventricular (i.c.v.) administration in the tail-flick test in mice. In acute i.c.v. studies, the bivalent ligands functioned as agonists with potencies ranging from 1.6- to 45-fold greater than morphine. In contrast, the monovalent mu agonist analogues were substantially more potent than the MDAN congeners and were essentially equipotent with one another and oxymorphone. Pretreatment with NTI decreased the ED(50) values for MDAN-19 to a greater degree than for MDAN-16 but had no effect on MDAN-21. Chronic i.c.v. studies revealed that MDAN ligands whose spacer was 16 atoms or longer produced less dependence than either morphine or mu monovalent control MA-19. On the other hand, both physical dependence and tolerance were suppressed at MDAN spacer lengths of 19 atoms or greater. These data suggest that physical interaction between the mu and delta opioid receptors modulates mu-mediated tolerance and dependence. Because MDAN-21 was found to be 50-fold more potent than morphine by the i.v. route (i.v.), it offers a previously uncharacterized approach for the development of analgesics devoid of tolerance and dependence.

Fig. 1.

Key pharmacophores: oxymorphone (1, μ agonist) and NTI (2, δ antagonist).

Fig. 2.

Final compounds.

Fig. 3.

Model for negative modulation of antinociception by bivalent ligands. The inactive (1) and active (2) states of the μ-δ heterodimer are in equilibrium with each other. Univalent binding of the μ agonist pharmacophore of the bivalent ligand to the μ opioid receptor recognition site leads to state 3. Bridging with concomitant transformation of the δ receptor to the antagonist state negatively modulates the μ receptor (4). Displacement of the δ antagonist pharmacophore of the bridged bivalent ligand by NTI disrupts tethering of the μ and δ receptors, thereby facilitating dissociation (5). This model envisages the heterodimers to be either in an active or inactive state but not in a mixed state, except when the associated receptors are held together by the bridged bivalent ligand.