Opioid agonist and antagonist bivalent ligands. The relationship between spacer length and selectivity at multiple opioid receptors

Abstract

Bivalent ligands containing the oxymorphamine or naltrexamine pharmacophores connected to spacers of varying length were synthesized and evaluated for their selectivity at mu, kappa, and delta opioid receptors. The oxymorphamine bivalent ligands (1-8) behaved as mu agonists on the electrically stimulated guinea pig ileum longitudinal muscle preparation (GPI). The spacer that conferred peak agonist activity in these series contains a total of four glycyl units (n = 2). Binding studies with guinea pig brain membranes showed a qualitatively similar profile at mu receptors as a function of spacer length. Also, delta receptor selectivity increased as the spacer was lengthened. The naltrexamine bivalent ligands (9-13) effectively antagonized the mu receptor agonist morphine in the GPI at the same optimal spacer length (n = 2) as in the agonist series. However, the peak antagonism of ethylketazocine, a kappa receptor agonist, occurred with the bivalent ligand 9 containing the shortest spacer (n = 0), and it was found that 9 is the most selective kappa antagonist in the series. While receptor binding roughly parallels that of kappa antagonist activity in the GPI, no correlation between binding and antagonist activity was observed at mu opioid receptors. The possible significance of these results is discussed.

Mu Opioids and Their Receptors: Evolution of a Concept

“…Similar results are seen with the hydrazide series as well. Thus, these agents do not simultaneously label two binding pockets, and their mechanism(s) of prolonged activity differ from that proposed by Portoghese for his bivalent ligands (Erez et al, 1982;Portoghese et al, 1986;Bolognesi et al, 1996).…”

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

“…Several studies have suggested that bivalent ligands may bridge associated opioid receptors. Bivalent ligands of opioid alkaloids (17)(18)(19)(20)(21)(22)(23)(24) and peptide agonists derived from enkephalins (25)(26)(27)(28) have been characterized as having increased opioid receptor potency and selectivity when compared to corresponding monovalent counterparts. More recently, bivalent ligands have been used as tools to further characterize ␦ and opioid receptor phenotypes.…”

Interaction of Bivalent Ligand KDN21 with Heterodimeric δ-κ Opioid Receptors in Human Embryonic Kidney 293 Cells

“…All three major types (␦, , and ) of opioid receptors share high homology (ϳ60%) and a highly conserved transmembrane domain (Knapp et al, 1995;Dhawan et al, 1996;Waldhoer et al, 2004). Before the development of opioid receptor cDNAs, a number of investigations suggested that opioid receptors physically interact with one another (Erez et al, 1982;Rothman and Westfall, 1982;Portoghese et al, 1986;Porreca et al, 1992;Traynor and Elliott, 1993). With the availability of cDNAs, a great number of studies using in vitro expression systems have afforded more convincing evidence for dimerization/oligomerization of opioid receptors (Jordan and Devi, 1999;George et al, 2000;Gomes et al, 2000;Ramsay et al, 2002).…”