Placement of Hydroxy Moiety on Pendant of Peptidomimetic Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy

Abstract

In an effort to expand the structure–activity relationship (SAR) studies of a series of mixed-efficacy opioid ligands, peptidomimetics that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics were evaluated. Compounds containing a methoxy or hydroxy moiety in the o- or m-positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the p-position decreased KOR affinity and reduced or eliminated efficacy at the mu opioid receptor (MOR). The results from a substituted 2-methylindanyl series aligned with the findings from the substituted benzyl series. Our studies culminated in the development of 8c, a mixed-efficacy MOR agonist/KOR agonist with subnanomolar binding affinity for both MOR and KOR.

Investigation of the μ‐ and κ‐opioid receptor activation by eight new synthetic opioids using the [35S]‐GTPγS assay: U‐47700, isopropyl U‐47700, U‐49900, U‐47931E, N‐methyl U‐47931E, U‐51754, U‐48520, and U‐48800

“…previously in different studies. 17,24,38,43,44 For the same reason, (II) and (IV) were also included in this study as additional MOR and KOR reference compounds. It needs to be noted here that because different reference compounds for MOR and KOR had to be used, the comparability of the data is limited.…”

“…15 Ligands, which are partial MOR agonists and full KOR agonists, are of interest for pharmaceutical research, since they probably have analgesic potential with a reduced risk of respiratory depression, tolerance, and abuse. 17 Other reported adverse effects resulting from recreational opioid consumption include hypothermia, sedation, anxiety, sweating, disorientation, drowsiness, nausea, obstipation, and miosis. 18,19 In 2009, the first NSO (o-desmethyltramadol) was reported to the EMCDDA Early Warning System.…”

Aromatic–Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability

“…Given the potential of these ligands to produce antinociception with reduced adverse effects, our lab has been developing a promising MOR-agonist/DOR-antagonist peptidomimetic series containing a tetrahydroquinoline (THQ) core. ,− As stability is an issue in this series, we recently reported an initial SAR study that showed it was possible to eliminate part of the tetrahydroquinoline core of these peptidomimetics and maintain the desired MOR-agonist/DOR-antagonist profile . While this approach proved useful for improving metabolic stability, we wished to enhance the potency and efficacy of these compounds at MOR and further increase their stability.…”

SAR Matrices Enable Discovery of Mixed Efficacy μ-Opioid Receptor Agonist Peptidomimetics with Simplified Structures through an Aromatic-Amine Pharmacophore

“…In the course of our development of a MOR-agonist/DOR-antagonist peptidomimetic series with a reduced abuse profile, − we found that the core tetrahydroquinoline structure in this series was a major metabolic liability. As such, we opted to simplify the core to a benzene ring .…”