Anitha Kopinathan
Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator N-(( trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1 H)-yl)ethyl)cyclohexyl)-1 H-indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D2 Receptor
Kopinathan, Anitha; Draper-Joyce, Christopher; Szabo, Monika; Christopoulos, Arthur; Scammells, Peter J; Lane, J Robert; Capuano, Ben
Authors
Christopher Draper-Joyce
Monika Szabo
Arthur Christopoulos
Peter J Scammells
Dr ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
ASSOCIATE PROFESSOR
Ben Capuano
Abstract
SB269652 (1) is a negative allosteric modulator of the dopamine D2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of "second generation" analogues of 1 whereby subtle modifications to the indole-2-carboxamide motif confer dramatic changes in functional affinity (5000-fold increase), cooperativity (100-fold increase), and a novel action to modulate dopamine efficacy. Thus, structural changes to this region of 1 allows the generation of a novel set of analogues with distinct pharmacological properties.
Citation
Kopinathan, A., Draper-Joyce, C., Szabo, M., Christopoulos, A., Scammells, P. J., Lane, J. R., & Capuano, B. (2019). Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator N-(( trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1 H)-yl)ethyl)cyclohexyl)-1 H-indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D2 Receptor. Journal of Medicinal Chemistry, 62(1), 371-377. https://doi.org/10.1021/acs.jmedchem.8b00192
Journal Article Type | Article |
---|---|
Acceptance Date | Jun 11, 2018 |
Online Publication Date | Jun 11, 2018 |
Publication Date | Jan 10, 2019 |
Deposit Date | Apr 22, 2020 |
Journal | Journal of Medicinal Chemistry |
Print ISSN | 0022-2623 |
Electronic ISSN | 1520-4804 |
Publisher | American Chemical Society |
Peer Reviewed | Peer Reviewed |
Volume | 62 |
Issue | 1 |
Pages | 371-377 |
DOI | https://doi.org/10.1021/acs.jmedchem.8b00192 |
Public URL | https://nottingham-repository.worktribe.com/output/1339506 |
Publisher URL | https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00192 |
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