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

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2021 Nov 13

PMID 34771099

Citations 6

Authors

Parthasaradhireddy Tanguturi

Vibha Pathak

Sixue Zhang

Omar Moukha-Chafiq

Corinne E Augelli-Szafran

John M Streicher

Affiliations

Soon will be listed here.

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 S-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.

Citing Articles

Descriptive molecular pharmacology of the δ opioid receptor (DOR): A computational study with structural approach.

Goode-Romero G, Dominguez L PLoS One. 2024; 19(7):e0304068.

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Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment.

Duron D, Tanguturi P, Campbell C, Chou K, Bejarano P, Gabriel K Sci Rep. 2024; 14(1):14715.

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SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis.

Iwai T, Mishima R, Hirayama S, Nakajima H, Oyama M, Watanabe S J Clin Med. 2024; 13(2).

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The role of opioid receptors in modulating Alzheimer's Disease.

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Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery II.

van Rijn R, Spetea M Molecules. 2022; 27(10).

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