Molecular determinants of biased agonism at the dopamine D₂ receptor

Journal of Medicinal Chemistry
Dietmar WeichertPeter Gmeiner

Abstract

The development of biased (functionally selective) ligands provides a formidable challenge in medicinal chemistry. In an effort to learn to design functionally selective molecular tools for the highly therapeutically relevant dopamine D2 receptor, we synthesized a collection of agonists based on structurally distinct head groups derived from canonical or atypical dopaminergic pharmacophores. The test compounds feature a long lipophilic appendage that was shown to mediate biased signaling. By employing functional assays and molecular dynamics simulations, we could show that atypical dopamine surrogates of type 1 and 2 promote biased signaling, while ligands built from classical dopaminergic head groups (type 3 and 4) typically elicit more balanced signaling profiles. Besides this, we found a strong influence of the stereochemistry of type 4 aminotetraline-derived agonists on functional selectivity at D2 receptors. Whereas the (S)-enantiomer behaved as a full agonist, the biased ligand (R)-4 induced poor G protein coupling but substantial β-arrestin recruitment.

References

Nov 1, 1991·The American Journal of Psychiatry·K L DavisM Davidson
Dec 1, 1985·Journal of Medicinal Chemistry·C KaiserJ P Hieble
Dec 22, 1983·Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character·J W Black, P Leff
Jan 1, 1983·Annual Review of Pharmacology and Toxicology·J G Cannon
Mar 26, 2003·Proceedings of the National Academy of Sciences of the United States of America·Niklas LindgrenGilberto Fisone
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
Nov 9, 2005·The Journal of Clinical Investigation·Keshava RajagopalHoward A Rockman
Nov 11, 2005·The Journal of Biological Chemistry·Sudha K ShenoyRobert J Lefkowitz
Jun 29, 2006·The Journal of Pharmacology and Experimental Therapeutics·Jonathan D UrbanRichard B Mailman
May 30, 2008·Frontiers in Bioscience : a Journal and Virtual Library·Kenneth D BrombergJohn Cijiang He
Sep 5, 2008·Proceedings of the National Academy of Sciences of the United States of America·Bernard MasriMarc G Caron
Mar 26, 2010·Journal of Computational Chemistry·Maarten G WolfGerrit Groenhof
Aug 31, 2010·The Journal of Pharmacology and Experimental Therapeutics·Jonathan D ViolinMichael W Lark
Dec 18, 2010·Molecular Pharmacology·Nuska TschammerPeter Gmeiner
Jan 14, 2011·Nature·Daniel M RosenbaumBrian K Kobilka
Feb 10, 2011·Pharmacological Reviews·Jean-Martin Beaulieu, Raul R Gainetdinov
Oct 18, 2011·Journal of Medicinal Chemistry·Julia KühhornPeter Gmeiner
Oct 26, 2011·Proceedings of the National Academy of Sciences of the United States of America·John A AllenJian Jin
Apr 12, 2012·Proceedings of the National Academy of Sciences of the United States of America·Rita RahmehSébastien Granier
Aug 4, 2012·ACS Chemical Neuroscience·Terry KenakinSteven Novick
Feb 16, 2013·Nature Reviews. Drug Discovery·Terry Kenakin, Arthur Christopoulos
Mar 23, 2013·Science·Daniel WackerRaymond C Stevens
May 18, 2013·Nature Reviews. Drug Discovery·Terry Kenakin, Arthur Christopoulos
Jun 5, 2013·Journal of Medicinal Chemistry·Christine HillerPeter Gmeiner

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Citations

Dec 17, 2016·Journal of Medicinal Chemistry·Mayako MichinoLei Shi
Feb 9, 2017·ACS Chemical Biology·Yuhong JiangDavid P Fairlie
Mar 2, 2017·Journal of Medicinal Chemistry·Dorothee MöllerPeter Gmeiner
Mar 17, 2017·Journal of Medicinal Chemistry·Alessandro BonifaziAmy Hauck Newman
May 11, 2017·Journal of Medicinal Chemistry·Barbara MännelPeter Gmeiner
Feb 7, 2018·Nature Communications·Hideaki YanoSergi Ferré
Nov 20, 2016·Molecular Pharmacology·Darren M RiddyChristopher J Langmead
Jun 27, 2017·Chemistry : a European Journal·Daniel LachmannBurkhard König
Jan 23, 2020·Scientific Reports·Marie GiengerPeter Gmeiner
Dec 16, 2020·Scientific Reports·Anni AllikaltDorothee Weikert
Jul 25, 2021·Cell Chemical Biology·Ee Von MooKirill A Martemyanov

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