Discovery of novel delta opioid receptor (Dor) inverse agonist and irreversible (non-competitive) antagonists

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

Research output: Contribution to journalArticlepeer-review

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, have been 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-45127/SRI-45128 as inverse agonists. Then, these compounds were evaluated in vitro for their binding affinity by radioligand binding and functional activity by35 S-GTPγS coupling and cAMP accumulation in cells expressing the human DOR. All three compounds demonstrated high binding affinity and selectivity at the DOR, and all three displayed their hypothesized molecular pharmacology of irreversible antagonism (SRI-9342) or inverse agonism (SRI-45127/SRI-45128). Together, these results demonstrate that we have 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.

Original languageEnglish (US)
Article number6693
JournalMolecules
Volume26
Issue number21
DOIs
StatePublished - Nov 1 2021
Externally publishedYes

Keywords

  • Delta opioid receptor
  • Inverse agonist
  • Irreversible antagonist
  • Molecular pharmacology
  • Non-competitive antagonist

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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