New 5-HT1A, 5HT2A and 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation

To reconstitute the molecular mechanisms underlying the cellular response to soluble receptor ligands, we have exploited a cell-free system that exhibits signal- (dioxin-)induced activation of the latent cytosolic dioxin receptor to an active DNA-binding species. The DNA-binding properties of the in vitro-activated form were qualitatively indistinguishable from those of in vivo-activated nuclear receptor extracted from dioxin-treated cells. In vitro activation of the receptor by dioxin was dose dependent and was mimicked by other dioxin receptor ligands in a manner that followed the rank order of their relative affinities for the receptor in vitro and their relative potencies to induce target gene transcription in vivo. Thus, in addition to triggering the initial release of inhibition of DNA binding and presumably allowing nuclear translocation, the ligand appears to play a crucial role in the direct control of the level of functional activity of a given ligand-receptor complex.

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GPR18, GPR55 and GPR119 (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f114/2019.4 ◽

2019 ◽

Vol 2019 (4) ◽

Author(s):

Stephen P.H. Alexander ◽

Andrew J. Irving

Keyword(s):

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Structural Similarity ◽

Synthetic Cannabinoid ◽

Receptor Ligands ◽

Orphan Status ◽

Endogenous Cannabinoid

GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [98]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.

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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

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.5b00100 ◽

2015 ◽

Vol 6 (8) ◽

pp. 1428-1435 ◽

Cited By ~ 22

Author(s):

Aaron M. Bender ◽

Nicholas W. Griggs ◽

Jessica P. Anand ◽

John R. Traynor ◽

Emily M. Jutkiewicz ◽

...

Keyword(s):

Asymmetric Synthesis ◽

Opioid Receptor ◽

Receptor Ligands ◽

Opioid Receptor Ligands ◽

Μ Opioid Receptor ◽

Mixed Efficacy ◽

Δ Opioid Receptor

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Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl—Simulated Interaction Patterns Confronted with Experimental Data

Molecules ◽

10.3390/molecules25204636 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4636 ◽

Cited By ~ 2

Author(s):

Sabina Podlewska ◽

Ryszard Bugno ◽

Lucja Kudla ◽

Andrzej J. Bojarski ◽

Ryszard Przewlocki

Keyword(s):

Molecular Modeling ◽

G Protein ◽

Opioid Receptor ◽

Pearson Correlation ◽

Interaction Patterns ◽

Receptor Ligands ◽

Opioid Receptor Ligands ◽

Dynamics Simulations

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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