Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands

Siavash Shahbazi Nia, Mohammad Anwar Hossain, Guangchen Ji, Sravan K. Jonnalagadda, Samuel Obeng, Md Ashrafur Rahman, Ali Ehsan Sifat, Saeideh Nozohouri, Collin Blackwell, Dhavalkumar Patel, Jon Thompson, Scott Runyon, Takato Hiranita, Christopher R. McCurdy, Lance McMahon, Thomas J. Abbruscato, Paul C. Trippier, Volker Neugebauer, Nadezhda A. German

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Using the structure of gliotoxin as a starting point, we have prepared two different chemotypes with selective affinity to the kappa opioid receptor (KOR). Using medicinal chemistry approaches and structure-activity relationship (SAR) studies, structural features required for the observed affinity were identified, and advanced molecules with favorable Multiparameter Optimization (MPO) and Ligand Lipophilicity (LLE) profiles were prepared. Using the Thermal Place Preference Test (TPPT), we have shown that compound2 blocks the antinociceptive effect of U50488, a known KOR agonist. Multiple reports suggest that modulation of KOR signaling is a promising therapeutic strategy in treating neuropathic pain (NP). As a proof-of-concept study, we tested compound 2 in a rat model of NP and recorded its ability to modulate sensory and emotional pain-related behaviors. Observed in vitro and in vivo results suggest that these ligands can be used to develop compounds with potential application as pain therapeutics.

Original languageEnglish (US)
Article number115309
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Jun 5 2023


  • Kappa opioid receptor
  • Neuropathic pain
  • Selectivity

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Organic Chemistry


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