Structural Evolution of a Bifunctional Mu-Opioid Receptor (MOR)/Delta-Opioid Receptor (DOR) Peptidomimetic as Nonaddictive Opioid Analgesics
Henry, Sean
2019
Abstract
Opioids have been used since antiquity for their ability to treat chronic and severe pain. However, their potent analgesic activity comes with severe side effects, including dependence, abuse, and even death by respiratory depression. Since these opioids are unmatched in their ability to treat pain, the development of alternatives without these negative side effects is sorely needed. While numerous strategies have been implemented, none yet have been successful. One promising new strategy involves targeting multiple different opioid receptors at the same time. More specifically, agonism at the µ-opioid receptor (MOR) with simultaneous activity at the δ-opioid receptor (DOR) can attenuate these negative side effects without compromising their analgesic effects. Previously, our lab has synthesized a peptidomimetic series that expresses a MOR-agonist/DOR-antagonist profile. Members of this series were found to express antinociception (a proxy measure for analgesia) in vivo without producing dependence, drug-seeking behavior, or tolerance to the antinociceptive effects. While these effects show great promise, they are only active upon intraperitoneal injection. Since chronic pain requires the administration of drug over a long period of time, enabling oral bioavailability is an important goal to transform these peptidomimetics into nonaddictive analgesics. Unfortunately, these ligands express very poor metabolic stability in mouse liver microsomes (MLM), and this instability is a product of the tetrahydroquinoline core structure of the peptidomimetic. This structure requires numerous synthetic steps to create, and its instability is manifest in several key intermediates. As such, this dissertation describes a series of structure-activity relationship (SAR) campaigns that sought to remove this unstable core while preserving our desired bifunctional opioid activity. Initially, we sought to convert the bicyclic tetrahydroquinoline core of our peptidomimetic series to a monocyclic aromatic core. This immediately resulted in improvements in metabolic stability, and no unstable intermediates were observed. However, the MOR-agonist properties of these ligands, necessary for inducing their analgesic properties, was lost in most analogues in this series, and while a few were better than morphine in vitro, they were not as potent or efficacious as our original peptidomimetics. Using the results of this SAR campaign as a springboard, we next sought to further improve their MOR-agonist properties and metabolic stability. To this end, a series of amine pendants were incorporated onto our monocyclic core analogues. These pendants managed to further improve the metabolic stability of these ligands. It was also discovered that these amines can induce high MOR-efficacy in our peptidomimetics, and when combined with an aromatic ring on the pendant, can induce high MOR-potency. This “aromatic-amine’ pharmacophore was found to produce highly potent and efficacious MOR-agonists, independent of the functionalization of the monocyclic aromatic core. In fact, MOR-superagonists with efficacy of up to 147% compared to the standard MOR-agonist DAMGO were discovered using this pharmacophore, and the pharmacophore even enabled elimination of the aromatic core entirely. All this came with consistent DOR-antagonism or weak partial DOR-agonism, in line with the opioid profile we sought to maintain. Herein, the SAR campaigns that led to the improvement in metabolic stability of these ligands are discussed, as well as the discovery and scope of this aromatic-amine pharmacophore. These campaigns significantly simplified the synthesis of the ligands, yielding no unstable intermediates and enabling a greater degree of structure diversification for future opioid ligands.Subjects
Nonaddictive Opioids Peptidomimetics Mu-opioid Receptor Agonist Delta-opioid Receptor Antagonist Metabolic Stability
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