Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Ligands

Abstract

N-Acetylation of the tetrahydroquinoline (THQ) core of a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10 mg/kg.

A Novel Mu-Delta Opioid Agonist Demonstrates Enhanced Efficacy With Reduced Tolerance and Dependence in Mouse Neuropathic Pain Models

“…1,44,51 This led several groups, including the Schiller, Mosberg, and Ananthan groups, to develop MOR-agonist/DOR-antagonist compounds. 4,5,19,20,38,39 These compounds produced anti-nociception in acute pain models with decreased tolerance and dependence, validating the approach. 3,5 Intriguingly however, dual MOR-DOR agonists have also been shown to be beneficial in a small number of studies.…”

Structural Simplification of a Tetrahydroquinoline-Core Peptidomimetic μ-Opioid Receptor (MOR) Agonist/δ-Opioid Receptor (DOR) Antagonist Produces Improved Metabolic Stability

“…These were made to mimic the substituents of the original THQ core without ring cyclization, or to mimic some N-acyl compounds that had utility in our previously reported THQ series. 16 These ligands were all weak partial MOR agonists and had reduced binding affinity at DOR compared to 5a . The ethyl aniline also displayed reduced affinity at MOR.…”

Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands

“…Herkinorin’s new alignment helped to reveal the front benzoyl of the template as a new μ-feature. Upon the recognition, we looked further at several other special μ-ligands able to align their key moieties with the front benzoyl (such as JOM-5 Mm 20 and Em-Mm 17 ), which greatly helped for validation of the front benzoyl as a new μ-feature (see the detailed discussions in Part 2 of this report).…”

“…20 (JOM-5 Mm) is a peptidomimetic ligand with mixed μ-agonist/δ-antagonist activity. 20 This ligand’s THQ scaffold along with the substituents can be aligned across three regions of the template: Regions A, D, and E (see Figure 24C). The alignment can account for the SAR data.…”