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

doi:10.1016/j.ejmech.2023.115309

Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands

Eur J Med Chem. 2023 Jun 5:254:115309. doi: 10.1016/j.ejmech.2023.115309. Epub 2023 Mar 29.

Authors

Siavash Shahbazi Nia¹, Mohammad Anwar Hossain¹, Guangchen Ji², Sravan K Jonnalagadda³, Samuel Obeng⁴, Md Ashrafur Rahman¹, Ali Ehsan Sifat¹, Saeideh Nozohouri¹, Collin Blackwell¹, Dhavalkumar Patel⁵, Jon Thompson⁶, Scott Runyon⁷, Takato Hiranita⁸, Christopher R McCurdy⁹, Lance McMahon¹, Thomas J Abbruscato¹, Paul C Trippier¹⁰, Volker Neugebauer¹¹, Nadezhda A German¹²

Affiliations

¹ Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA.
² Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
³ Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
⁴ Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University, Birmingham, AL, 35229, USA.
⁵ Office of Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA.
⁶ Veterinary School of Medicine, Texas Tech University, Amarillo, TX, 79106, USA.
⁷ Reserach Triangle Institute, Research Triangle Park, Durham, NC, 27709, USA.
⁸ Department of Pharmacology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
⁹ Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
¹⁰ Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA; UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, NE, 68106, USA.
¹¹ Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
¹² Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA. Electronic address: nadezhda.german@ttuhsc.edu.

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: Kappa opioid receptor; Neuropathic pain; Selectivity.

MeSH terms

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / chemistry
Analgesics, Opioid / chemistry
Animals
Diketopiperazines
Ligands
Neuralgia*
Rats
Receptors, Opioid*
Receptors, Opioid, kappa

Substances

Analgesics, Opioid
Diketopiperazines
Ligands
Receptors, Opioid
Receptors, Opioid, kappa
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer

Abstract

MeSH terms

Substances

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