Dr SHAILESH MISTRY Shailesh.Mistry@nottingham.ac.uk
ASSOCIATE PROFESSOR
Dr SHAILESH MISTRY Shailesh.Mistry@nottingham.ac.uk
ASSOCIATE PROFESSOR
Jeremy Shonberg
Christopher J. Draper-Joyce
Carmen Klein Herenbrink
Mayako Michino
Lei Shi
Arthur Christopoulos
Ben Capuano
Peter J. Scammells
Dr ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
ASSOCIATE PROFESSOR
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.
Mistry, S. N., Shonberg, J., Draper-Joyce, C. J., Klein Herenbrink, C., Michino, M., Shi, L., Christopoulos, A., Capuano, B., Scammells, P. J., & 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
Journal Article Type | Article |
---|---|
Online Publication Date | Aug 28, 2015 |
Publication Date | Sep 10, 2015 |
Deposit Date | Oct 9, 2015 |
Publicly Available Date | Oct 9, 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 |
DOI | https://doi.org/10.1021/acs.jmedchem.5b00585 |
Public URL | https://nottingham-repository.worktribe.com/output/759243 |
Publisher URL | http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00585 |
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/10.1021/acs.jmedchem.5b00585 |
jm-2015-005859.R2 - JMC 58(17) 2015 6819.pdf
(1.3 Mb)
PDF
Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10
(2021)
Journal Article
About Repository@Nottingham
Administrator e-mail: discovery-access-systems@nottingham.ac.uk
This application uses the following open-source libraries:
Apache License Version 2.0 (http://www.apache.org/licenses/)
Apache License Version 2.0 (http://www.apache.org/licenses/)
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2025
Advanced Search