A Bivalent Ligand (KDAN-18) Containing δ-Antagonist and κ-Agonist Pharmacophores Bridges δ₂ and κ₁ Opioid Receptor Phenotypes

Abstract

To characterize delta- and kappa-opioid receptor phenotypes, bivalent ligands (KDAN series) containing delta-antagonist (naltrindole) and kappa(1)-agonist (ICI-199,441) pharmacophores were synthesized and evaluated by the intrathecal route using the mouse tail-flick assay and binding studies. The data have suggested that KDAN-18 (2) bridges phenotypic delta(2)- and kappa(1)-receptors. A conceptual model is presented to explain the organizational differences between the opioid receptors that give rise to the phenotypes (delta(1), delta(2), kappa(1), kappa(2)).

In Vivo Characterization of (−)(−)MCL-144 and (+)(−)MCL-193: Isomeric, Bivalent Ligands with Mu/Kappa Agonist Properties

“…It is possible that (−)(−)MCL-145, due to the shorter length of the spacer region, is interacting with the receptors in a manner which is different from (−)(−)MCL-144. It is suggested that (−)(−)MCL-145 may not be bridging between two receptors in a dimer since previous studies indicated a linker length of 8-20 atoms was optimal for binding affinity (2,3). Preliminary metabolism studies conducted in the rat brain homogenate indicated that (−) (−)MCL-145 was rapidly metabolized to (−)MCL-101, with a half-life of 38 min, while the half-life for (−)(−)MCL-144 was 70 min.…”

“…However, such a compound has remained elusive. One approach has been to synthesize ligands which were designed to bridge two opioid receptors, or dimers (2,3).…”

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

“…More recently, bivalent ligands have been used as tools to further characterize ␦ and opioid receptor phenotypes. Specifically, unique bivalent probes that target ␦ 1 -2 heterodimers (29) or associated ␦ 2 -1 opioid receptors (30) have been reported.…”

A κ Opioid Pharmacophore Becomes a Spinally Selective κ-δ Agonist When Modified with a Basic Extender Arm

“…5,6 Such ligands whose spacer is in the range of 18-21 atoms have pharmacological properties that are consistent with the activation or antagonism of heteromeric opioid receptors in vivo and in vitro. 7 Thus, bivalent ligands have been reported for targeting of heteromeric μ-κ, κ-δ, and μ-δ opioid receptors.…”

“…Significantly, the spacer length for the presumed bridging of receptors is in the range of 16-21 atoms for these bivalent ligands, which is of sufficient length for cross-linking the receptor protomers in an oligomeric array. [5][6][7][8][9][10] Different pharmacological selectivity profiles upon intrathecal (i.t.) versus intracerebroventricular (i.c.v.)…”