Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists.

Parthasaradhireddy Tanguturi,Vibha Pathak,Corinne Augelli-Szafran,John Streicher,Sixue Zhang,Omar Moukha-Chafiq

doi:10.3390/molecules26216693

Parthasaradhireddy Tanguturi, Vibha Pathak + Show 4 more

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https://doi.org/10.3390/molecules26216693

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Abstract

The delta opioid receptor (DOR) is a crucial receptor system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, and DOR-neutral antagonists, such as naltrindole, were developed to investigate the DOR in vivo and as potential therapeutics for pain and depression. However, few inverse agonists and non-competitive/irreversible antagonists have been developed, and none are widely available. This leaves a gap in our pharmacological toolbox and limits our ability to investigate the biology of this receptor. Thus, we designed and synthesized the novel compounds SRI-9342 as an irreversible antagonist and SRI-45128 as an inverse agonist. These compounds were then evaluated in vitro for their binding affinity by radioligand binding, their functional activity by 35S-GTPγS coupling, and their cAMP accumulation in cells expressing the human DOR. Both compounds demonstrated high binding affinity and selectivity at the DOR, and both displayed their hypothesized molecular pharmacology of irreversible antagonism (SRI-9342) or inverse agonism (SRI-45128). Together, these results demonstrate that we have successfully designed new inverse agonists and irreversible antagonists of the DOR based on a novel chemical scaffold. These new compounds will provide new tools to investigate the biology of the DOR or even new potential therapeutics.

Highlights

G-protein coupled receptors (GPCRs) are a superfamily of integral plasma membrane proteins and are involved in a broad array of signaling pathways and subsequent physiological processes
The three delta opioid receptor (DOR) ligands SRI-9342 and SRI-45127/SRI-45128 were designed based on our previously published computational docking studies of the same scaffold core [15]. When this core binds to the orthosteric site of DOR, the right-hand side indole moiety would face the extracellular opening of the binding pocket and be adjacent to functionally important K214 of DOR [16], which is a potentially reactive residue
The cyclopropyl group of the scaffold would face the bottom of the binding pocket and form hydrophobic contact with W274 of DOR, which is an important residue responsible for the switch between agonism/antagonism [16,17]

Summary

Introduction

G-protein coupled receptors (GPCRs) are a superfamily of integral plasma membrane proteins and are involved in a broad array of signaling pathways and subsequent physiological processes. Unlike competitive antagonists, which commonly affect the amount of agonist necessary to achieve a maximal response but will not affect the magnitude of that maximal response, non-competitive antagonists decrease the level of the maximum response which can be accomplished by any amount of agonist. This unique property receives the name as “non-competitive” because the effects cannot be overcome no matter how much agonist is present. One example is the commonly used beta-funaltrexamine, which is selective for the mu opioid receptor [4] A few such ligands have been reported for the DOR, and none are widely available. These include a naphthalene-dialdehyde modification of 6 -aminonaltrindole [5] and 5 -naltrindole-isothiocyanate [6]

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