Asymmetric Synthesis and in Vitro and in Vivo Activity of Tetrahydroquinolines Featuring a Diverse Set of Polar Substitutions at the 6 Position as Mixed-Efficacy μ Opioid Receptor/δ Opioid Receptor Ligands

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In this study, a comprehensive molecular modeling protocol was developed to explain the observed activity profiles of selected µ opioid receptor agents: two G protein-biased µ opioid receptor agonists (PZM21 and SR-17018), unbiased morphine, and the β-arrestin-2-biased agonist, fentanyl. The study involved docking and molecular dynamics simulations carried out for three crystal structures of the target at a microsecond scale, followed by the statistical analysis of ligand–protein contacts. The interaction frequency between the modeled compounds and the subsequent residues of a protein during the simulation was also correlated with the output of in vitro and in vivo tests, resulting in the set of amino acids with the highest Pearson correlation coefficient values. Such indicated positions may serve as a guide for designing new G protein-biased ligands of the µ opioid receptor.

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Signaling Properties of Structurally Diverse Kappa Opioid Receptor Ligands: Toward in Vitro Models of in Vivo Responses

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.9b00195 ◽

2019 ◽

Vol 10 (8) ◽

pp. 3590-3600 ◽

Cited By ~ 12

Author(s):

Amelia D. Dunn ◽

Brian Reed ◽

Jose Erazo ◽

Ariel Ben-Ezra ◽

Mary Jeanne Kreek

Keyword(s):

Opioid Receptor ◽

In Vitro Models ◽

Kappa Opioid Receptor ◽

Receptor Ligands ◽

Kappa Opioid ◽

Opioid Receptor Ligands

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

Molecules ◽

10.3390/molecules26237236 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7236

Author(s):

Yazan J. Meqbil ◽

Hongyu Su ◽

Robert J. Cassell ◽

Kendall L. Mores ◽

Anna M. Gutridge ◽

...

Keyword(s):

Opioid Receptor ◽

Clinical Drug Development ◽

In Vitro Characterization ◽

Opioid Receptor Agonist ◽

Negative Allosteric Modulator ◽

Δ Opioid Receptor ◽

Clinical Drug

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.

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