Ligand-Based Discovery of a New Scaffold for Allosteric Modulation of the μ-Opioid Receptor

Journal of Chemical Information and Modeling
Paola BisignanoMarta Filizola

Abstract

With the hope of discovering effective analgesics with fewer side effects, attention has recently shifted to allosteric modulators of the opioid receptors. In the past two years, the first chemotypes of positive or silent allosteric modulators (PAMs or SAMs, respectively) of μ- and δ-opioid receptor types have been reported in the literature. During a structure-guided lead optimization campaign with μ-PAMs BMS-986121 and BMS-986122 as starting compounds, we discovered a new chemotype that was confirmed to display μ-PAM or μ-SAM activity depending on the specific substitutions as assessed by endomorphin-1-stimulated β-arrestin2 recruitment assays in Chinese Hamster Ovary (CHO)-μ PathHunter cells. The most active μ-PAM of this series was analyzed further in competition binding and G-protein activation assays to understand its effects on ligand binding and to investigate the nature of its probe dependence.

References

Sep 24, 1999·European Journal of Pharmacology·K O LeeJ R Traynor
Mar 23, 2012·Nature·Aashish ManglikSébastien Granier
May 4, 2012·Molecular Pharmacology·Guadalupe RiveroEamonn Kelly
May 17, 2012·Journal of Chemical Information and Modeling·John J IrwinRyan G Coleman
Mar 2, 2013·Current Pharmaceutical Design·Mariana SpeteaHelmut Schmidhammer
Jun 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Neil T BurfordAndrew Alt
Oct 1, 2013·Neurobiology of Disease·Hilary Highfield Nickols, P Jeffrey Conn
Jan 28, 2014·British Journal of Pharmacology·G L ThompsonM Canals
May 7, 2014·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Gavril W Pasternak
Dec 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·Kathryn E Livingston, John R Traynor
Aug 8, 2015·Nature·Weijiao HuangBrian K Kobilka

❮ Previous
Next ❯

Citations

Jun 3, 2016·Journal of Chemical Information and Modeling·Cleber C Melo-FilhoCarolina H Andrade
Apr 4, 2017·ACS Chemical Neuroscience·Michael RemesicYeon Sun Lee
Apr 19, 2017·British Journal of Pharmacology·Kathryn E Livingston, John R Traynor
Dec 26, 2016·Peptides·Richard J Bodnar
Jan 23, 2016·Journal of Laboratory Automation·Joe OlechnoLynn Rasmussen
May 31, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Metehan IlterOzge Sensoy
Dec 14, 2017·Molecular Pharmacology·Kathryn E LivingstonJohn R Traynor
Nov 28, 2020·Cellular and Molecular Neurobiology·Cherkaouia KibalyCatherine M Cahill
Nov 15, 2020·International Journal of Molecular Sciences·Damian BartuziDariusz Matosiuk
Apr 14, 2021·Proceedings of the National Academy of Sciences of the United States of America·Ram KandasamyJohn R Traynor
Mar 24, 2021·Annual Review of Biochemistry·Tao Che, Bryan L Roth

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

© 2021 Meta ULC. All rights reserved