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Papers of the Week

Papers: 8 Apr 2023 - 14 Apr 2023

Basic Science

Animal Studies, Molecular/Cellular, Pharmacology/Drug Development

2023 Mar 29

Eur J Med Chem



Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands.


Shahbazi Nia S, Hossain MA, Ji G, Jonnalagadda SK, Obeng S, Rahman MA, Sifat AE, Nozohouri S, Blackwell C, Patel D, Thompson J, Runyon S, Hiranita T, McCurdy CR, McMahon L, Abbruscato TJ, Trippier PC, Neugebauer V, German NA


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.