Faculty, Staff and Student Publications

Language

English

Publication Date

6-5-2023

Journal

European Journal of Medicinal Chemistry

DOI

10.1016/j.ejmech.2023.115309

PMID

37054561

PMCID

PMC10634475

PubMedCentral® Posted Date

11-9-2023

PubMedCentral® Full Text Version

Author MSS

Abstract

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.

Keywords

Animals, Rats, Analgesics, Opioid, Diketopiperazines, Ligands, Neuralgia, Receptors, Opioid, Receptors, Opioid, kappa, 3, 4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer, Kappa opioid receptor, Selectivity, Neuropathic pain

Published Open-Access

yes

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