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

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

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English (US)
Article number	115309
Journal	European Journal of Medicinal Chemistry
Volume	254
DOIs	https://doi.org/10.1016/j.ejmech.2023.115309
State	Published - Jun 5 2023

Keywords

Kappa opioid receptor
Neuropathic pain
Selectivity

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2023.115309

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Shahbazi Nia, S., Hossain, M. A., Ji, G., Jonnalagadda, S. K., Obeng, S., Rahman, M. A., Sifat, A. E., Nozohouri, S., Blackwell, C., Patel, D., Thompson, J., Runyon, S., Hiranita, T., McCurdy, C. R., McMahon, L., Abbruscato, T. J., Trippier, P. C., Neugebauer, V., & German, N. A. (2023). Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands. European Journal of Medicinal Chemistry, 254, Article 115309. https://doi.org/10.1016/j.ejmech.2023.115309

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 2023, 'Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands', European Journal of Medicinal Chemistry, vol. 254, 115309. https://doi.org/10.1016/j.ejmech.2023.115309

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title = "Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands",

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",

author = "{Shahbazi Nia}, Siavash and Hossain, {Mohammad Anwar} and Guangchen Ji and Jonnalagadda, {Sravan K.} and Samuel Obeng and Rahman, {Md Ashrafur} and Sifat, {Ali Ehsan} and Saeideh Nozohouri and Collin Blackwell and Dhavalkumar Patel and Jon Thompson and Scott Runyon and Takato Hiranita and McCurdy, {Christopher R.} and Lance McMahon and Abbruscato, {Thomas J.} and Trippier, {Paul C.} and Volker Neugebauer and German, {Nadezhda A.}",

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doi = "10.1016/j.ejmech.2023.115309",

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AU - Shahbazi Nia, Siavash

AU - Hossain, Mohammad Anwar

AU - Ji, Guangchen

AU - Jonnalagadda, Sravan K.

AU - Obeng, Samuel

AU - Rahman, Md Ashrafur

AU - Sifat, Ali Ehsan

AU - Nozohouri, Saeideh

AU - Blackwell, Collin

AU - Patel, Dhavalkumar

AU - Thompson, Jon

AU - Runyon, Scott

AU - Hiranita, Takato

AU - McCurdy, Christopher R.

AU - McMahon, Lance

AU - Abbruscato, Thomas J.

AU - Trippier, Paul C.

AU - Neugebauer, Volker

AU - German, Nadezhda A.

PY - 2023/6/5

Y1 - 2023/6/5

N2 - 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.

AB - 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.

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Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands

Abstract

Keywords

ASJC Scopus subject areas

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