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

Abstract

We previously reported a novel SAR campaign that converted a metabolically unstable series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist bicyclic core peptidomimetics with promising analgesic activity and reduced abuse liabilities into a more stable series of benzylic core analogues. Herein, we expanded the SAR of that campaign and determined that the incorporation of amines into the benzylic pendant produces enhanced MOR-efficacy in this series, whereas the reincorporation of an aromatic ring into the pendant enhanced MOR-potency. Two compounds, which contain a piperidine (14) or an isoindoline (17) pendant, retained the desired opioid profile in vitro, possessed metabolic half-lives of greater than 1 h in mouse liver microsomes (MLMs), and were active antinociceptive agents in the acetic acid stretch assay (AASA) at subcutaneous doses of 1 mg/kg.

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

“…The syntheses of these new analogues followed the same synthetic pathway described previously and are shown in Scheme A. Here, different ethers were introduced by alkylating methyl 3-formyl-4-hydroxybenzoate ( 1 ) using appropriate alkyl iodides or bromides.…”

“…Since lowering cLogP is known to reduce metabolism by CYP enzymes, we took the ether with the greatest level of MOR-agonism and replaced the benzyl pendant with a cyclic amine (Figure B). This was found to improve MOR-efficacy while also improving the metabolic stability of these ligands . Furthermore, the addition of an aromatic ring onto this cyclic amine pendant improved MOR-potency at the cost of some of the improved metabolic stability.…”

Design, Synthesis, and Molecular Mechanism Studies of N-Phenylisoxazoline-thiadiazolo[3,4-a]pyridazine Hybrids as Protoporphyrinogen IX Oxidase Inhibitors

“…The three-dimensional (3D) structures of compounds 1 – 5 and fluthiacet-methyl were constructed and optimized using Sybyl 6.9 (Tripos, Inc.); then, the optimized structures were used for the cLog P calculation. , …”

“…The three-dimensional (3D) structures of compounds 1−5 and fluthiacet-methyl were constructed and optimized using Sybyl 6.9 (Tripos, Inc.); then, the optimized structures were used for the cLogP calculation. 32,33 Structural Alignments. The structures of protoporphyrinogen IX and the N-phenylisoxazoline-thiadiazolo[3,4-a] pyridazine scaffold were constructed and optimized using Sybyl 6.9, the alignment of two molecules was performed using Open3DALIGN, 34 and the results were visualized using PYMOL 1.3.…”

Synthesis and Structure–Activity Relationships of 5′-Aryl-14-alkoxypyridomorphinans: Identification of a μ Opioid Receptor Agonist/δ Opioid Receptor Antagonist Ligand with Systemic Antinociceptive Activity and Diminished Opioid Side Effects

“…However, the use of opioid analgesics is associated with severe limiting side effects including abuse liability, respiratory depression, constipation, and development of tolerance and dependence. − Therefore, considerable effort has been expended on the discovery of novel opioid analgesics that are as efficacious as the prototypic opioid analgesic morphine but possessing reduced side effects. Opioid drugs exert their analgesic effects through binding and activation of the three opioid receptor subtypes, namely, the μ opioid receptor (MOR), the δ opioid receptor (DOR), and the κ opioid receptor (KOR). , Several lines of evidence suggest that there are physical and/or functional interactions between these G-protein coupled receptors, and molecules that interact with multiple receptors may prove advantageous in the search for opioid ligands with diminished side effect profiles. − Considerable evidence from gene knockout/knockdown studies and studies using pharmacological probes suggests that activation of the MOR with simultaneous inhibition of the DOR leads to MOR-mediated analgesic activity with diminished development of tolerance, dependence, and potentially other side effects. ,− Based on these observations, we , and others ,− pursued the development of mixed function ligands possessing a MOR agonist/DOR antagonist profile of activity using peptidic, peptidomimetic, and nonpeptide opioid templates. Exemplary MOR agonist/DOR antagonist ligands evaluated in animal models are shown in Figure .…”