Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator N-((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D2 Receptor
| Autor: | Ben Capuano, Christopher J Draper-Joyce, J. Robert Lane, Peter J. Scammells, Monika Szabo, Arthur Christopoulos, Anitha Kopinathan |
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| Rok vydání: | 2018 |
| Předmět: |
Indole test
0303 health sciences Allosteric modulator Stereochemistry medicine.drug_class Chemistry Allosteric regulation Biological activity Carboxamide Cooperativity 01 natural sciences 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences Dopamine receptor D2 Drug Discovery medicine Molecular Medicine Structure–activity relationship 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 62:371-377 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b00192 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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