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Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand

Mistry, Shailesh N.; Shonberg, Jeremy; Draper-Joyce, Christopher J.; Klein Herenbrink, Carmen; Michino, Mayako; Shi, Lei; Christopoulos, Arthur; Capuano, Ben; Scammells, Peter J.; Lane, J. Robert

Authors

Jeremy Shonberg

Christopher J. Draper-Joyce

Carmen Klein Herenbrink

Mayako Michino

Lei Shi

Arthur Christopoulos

Ben Capuano

Peter J. Scammells

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor



Abstract

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R.

Journal Article Type Article
Publication Date Sep 10, 2015
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 58
Issue 17
Pages 6819-6843
APA6 Citation Mistry, S. N., Shonberg, J., Draper-Joyce, C. J., Klein Herenbrink, C., Michino, M., Shi, L., …Lane, J. R. (2015). Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand. Journal of Medicinal Chemistry, 58(17), 6819-6843. https://doi.org/10.1021/acs.jmedchem.5b00585
DOI https://doi.org/10.1021/acs.jmedchem.5b00585
Publisher URL http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00585
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi...21/acs.jmedchem.5b00585

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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