Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand

Mistry, Shailesh N. and Shonberg, Jeremy and Draper-Joyce, Christopher J. and Klein Herenbrink, Carmen and Michino, Mayako and Shi, Lei and Christopoulos, Arthur and Capuano, Ben and Scammells, Peter J. and Lane, J. Robert (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). pp. 6819-6843. ISSN 0022-2623

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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.

Item Type: Article
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
Schools/Departments: University of Nottingham UK Campus > Faculty of Science > School of Pharmacy
Identification Number: https://doi.org/10.1021/acs.jmedchem.5b00585
Depositing User: Mistry, Dr Shailesh
Date Deposited: 09 Oct 2015 10:29
Last Modified: 26 Sep 2016 15:30
URI: http://eprints.nottingham.ac.uk/id/eprint/30315

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