European journal of medicinal chemistry · 2023
Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands.
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Shahbazi Nia Siavash, Hossain Mohammad Anwar, Ji Guangchen, Jonnalagadda Sravan K, Obeng Samuel, Rahman Md Ashrafur, Sifat Ali Ehsan, Nozohouri Saeideh, Blackwell Collin, Patel Dhavalkumar, Thompson Jon, Runyon Scott, Hiranita Takato, McCurdy Christopher R, McMahon Lance, Abbruscato Thomas J, Trippier Paul C, Neugebauer Volker, German Nadezhda A
Аннотация
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.