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

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: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=29890071&retmode=ref&cmd=prlinks
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00192