Studies on Diketopiperazine and Dipeptide Analogs as Opioid Receptor Ligands

53 Pages Posted: 6 Feb 2023

See all articles by Siavash Shahbazi Nia

Siavash Shahbazi Nia

Texas Tech University Health Sciences Center

Mohammad Anwar Hossain

Texas Tech University Health Sciences Center

Guangcheng Ji

Texas Tech University Health Sciences Center

Sravan K. Jonnalagadda

University of Nebraska Medical Center

Samuel Obeng

Samford University

Md Ashrafur Rahman

Texas Tech University Health Sciences Center

Ali Ehsan Sifat

Texas Tech University Health Sciences Center

Saeideh Nozohouri

Texas Tech University Health Sciences Center

Collin Blackwell

Texas Tech University Health Sciences Center

Dhavalkumar Patel

Texas Tech University Health Sciences Center

Jon Thompson

Texas Tech University

Scott Runyon

RTI International

Takato Hiranita

University of Texas Health San Antonio

Christopher R. McCurdy

University of Florida

Lance McMahon

Texas Tech University Health Sciences Center

Thomas Abbruscato

Texas Tech University Health Sciences Center

Paul C. Trippier

University of Nebraska Medical Center

Volker Neugebauer

Texas Tech University Health Sciences Center

Nadezhda A. German

Texas Tech University Health Sciences Center

Date Written: January 19, 2023

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 compound 2 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, selectivity, neuropathic pain

Suggested Citation

Shahbazi Nia, Siavash and Hossain, Mohammad Anwar and Ji, Guangcheng and Jonnalagadda, Sravan K. and Obeng, Samuel and Rahman, Md Ashrafur and Sifat, Ali Ehsan and Nozohouri, Saeideh and Blackwell, Collin and Patel, Dhavalkumar and Thompson, Jon and Runyon, Scott and Hiranita, Takato and McCurdy, Christopher R. and McMahon, Lance and Abbruscato, Thomas and Trippier, Paul C. and Neugebauer, Volker and German, Nadezhda A., Studies on Diketopiperazine and Dipeptide Analogs as Opioid Receptor Ligands (January 19, 2023). Available at SSRN: https://ssrn.com/abstract=4329575 or http://dx.doi.org/10.2139/ssrn.4329575

Siavash Shahbazi Nia

Texas Tech University Health Sciences Center ( email )

Mohammad Anwar Hossain

Texas Tech University Health Sciences Center ( email )

Guangcheng Ji

Texas Tech University Health Sciences Center ( email )

United States

Sravan K. Jonnalagadda

University of Nebraska Medical Center ( email )

Samuel Obeng

Samford University ( email )

800 Lakeshore Drive
Birmingham, AL 35229
United States

Md Ashrafur Rahman

Texas Tech University Health Sciences Center ( email )

Ali Ehsan Sifat

Texas Tech University Health Sciences Center ( email )

Saeideh Nozohouri

Texas Tech University Health Sciences Center ( email )

Collin Blackwell

Texas Tech University Health Sciences Center ( email )

Dhavalkumar Patel

Texas Tech University Health Sciences Center ( email )

Jon Thompson

Texas Tech University ( email )

2500 Broadway
Lubbock, TX 79409
United States

Scott Runyon

RTI International ( email )

PO Box 12194
Washington, DC 20036-3209
United States

Takato Hiranita

University of Texas Health San Antonio ( email )

Christopher R. McCurdy

University of Florida ( email )

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Lance McMahon

Texas Tech University Health Sciences Center ( email )

Thomas Abbruscato

Texas Tech University Health Sciences Center ( email )

Paul C. Trippier

University of Nebraska Medical Center ( email )

Volker Neugebauer

Texas Tech University Health Sciences Center ( email )

United States

Nadezhda A. German (Contact Author)

Texas Tech University Health Sciences Center ( email )

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