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Article

Identification of a Novel Delta Opioid Receptor Agonist Chemotype with Potential Negative Allosteric Modulator Capabilities

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Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
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Computational Interdisciplinary Life Sciences, Purdue University, West Lafayette, IN 47907, USA
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Department of Chemistry, College of Science, Purdue University, West Lafayette, IN 47907, USA
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Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
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Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Jay McLaughlin
Molecules 2021, 26(23), 7236; https://doi.org/10.3390/molecules26237236
Received: 5 November 2021 / Revised: 25 November 2021 / Accepted: 27 November 2021 / Published: 29 November 2021
The δ-opioid receptor (δOR) holds great potential as a therapeutic target. Yet, clinical drug development, which has focused on δOR agonists that mimic the potent and selective tool compound SNC80 have largely failed. It has increasingly become apparent that the SNC80 scaffold carries with it potent and efficacious β-arrestin recruitment. Here, we screened a relatively small (5120 molecules) physical drug library to identify δOR agonists that underrecruit β-arrestin, as it has been suggested that compounds that efficaciously recruit β-arrestin are proconvulsant. The screen identified a hit compound and further characterization using cellular binding and signaling assays revealed that this molecule (R995045, compound 1) exhibited ten-fold selectivity over µ- and κ-opioid receptors. Compound 1 represents a novel chemotype at the δOR. A subsequent characterization of fourteen analogs of compound 1, however did not identify a more potent δOR agonist. Computational modeling and in vitro characterization of compound 1 in the presence of the endogenous agonist leu-enkephalin suggest compound 1 may also bind allosterically and negatively modulate the potency of Leu-enkephalin to inhibit cAMP, acting as a ‘NAM-agonist’ in this assay. The potential physiological utility of such a class of compounds will need to be assessed in future in vivo assays. View Full-Text
Keywords: chemotype; high-throughput screen; delta opioid receptor; allosteric modulation; beta-arrestin; molecular dynamics chemotype; high-throughput screen; delta opioid receptor; allosteric modulation; beta-arrestin; molecular dynamics
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MDPI and ACS Style

Meqbil, Y.J.; Su, H.; Cassell, R.J.; Mores, K.L.; Gutridge, A.M.; Cummins, B.R.; Chen, L.; van Rijn, R.M. Identification of a Novel Delta Opioid Receptor Agonist Chemotype with Potential Negative Allosteric Modulator Capabilities. Molecules 2021, 26, 7236. https://doi.org/10.3390/molecules26237236

AMA Style

Meqbil YJ, Su H, Cassell RJ, Mores KL, Gutridge AM, Cummins BR, Chen L, van Rijn RM. Identification of a Novel Delta Opioid Receptor Agonist Chemotype with Potential Negative Allosteric Modulator Capabilities. Molecules. 2021; 26(23):7236. https://doi.org/10.3390/molecules26237236

Chicago/Turabian Style

Meqbil, Yazan J., Hongyu Su, Robert J. Cassell, Kendall L. Mores, Anna M. Gutridge, Benjamin R. Cummins, Lan Chen, and Richard M. van Rijn. 2021. "Identification of a Novel Delta Opioid Receptor Agonist Chemotype with Potential Negative Allosteric Modulator Capabilities" Molecules 26, no. 23: 7236. https://doi.org/10.3390/molecules26237236

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