Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series.
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.
Daniels
David J
DJ
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Lenard
Natalie R
NR
Etienne
Chris L
CL
Law
Ping-Yee
PY
Roerig
Sandra C
SC
Portoghese
Philip S
PS
D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008956:Models, Chemical; D015233:Models, Statistical; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000737:chemistry; D017450:Receptors, Opioid, mu / Q000737:chemistry; D013997:Time Factors
D000700:Analgesics; D000701:Analgesics, Opioid; D008024:Ligands; D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D009020:Morphine; C055382:naltrindole