Identification and Characterization of the First Selective Y4 Receptor Positive Allosteric Modulator.
J Med Chem
; 60(17): 7605-7612, 2017 09 14.
Article
em En
| MEDLINE
| ID: mdl-28795803
ABSTRACT
The human Y4 receptor (Y4R) and its cognate ligand, pancreatic polypeptide (PP), are involved in the regulation of energy expenditure, satiety, and food intake. This system represents a potential target for the treatment of metabolic diseases and has been extensively investigated and validated in vivo. Here, we present the compound tBPC (tert-butylphenoxycyclohexanol), a novel and selective Y4R positive allosteric modulator that potentiates Y4R activation in G-protein signaling and arrestin3 recruitment experiments. The compound has no effect on the binding of the orthosteric ligands, implying its allosteric mode of action at the Y4R and evidence for a purely efficacy-driven positive allosteric modulation. Finally, the ability of tBPC to selectively potentiate Y4R agonism initiated by PP was confirmed in mouse descending colon mucosa preparations expressing native Y4R, demonstrating Y4R positive allosteric modulation in vitro.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Receptores de Neuropeptídeo Y
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Proteínas de Ligação ao GTP
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Cicloexanóis
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Regulação Alostérica
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article