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

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.

Citation

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