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HBK-17, a 5-HT1A receptor ligand with anxiolytic-like activity, preferentially activates ß-arrestin signaling

Authors :
Jarosław Śmieja
Monika Głuch-Lutwin
Agata Siwek
Adrian Olczyk
Karolina Pytka
Katarzyna Pańczyk
Anna M. Waszkielewicz
Henryk Marona
Magdalena Smolik
Jacek Sapa
Adam Galuszka
Elżbieta Żmudzka
Kinga Sałaciak
Marcin Kołaczkowski
Barbara Filipek
Maria Walczak
Katarzyna Niemczyk
Source :
Frontiers in Pharmacology, Frontiers in Pharmacology, Vol 9 (2018)
Publication Year :
2018

Abstract

Numerous studies have proven that both stimulation and blockade of 5-HT1A and the blockade of 5-HT7 receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic-like activity, as well as the possible mechanism of action of 1-[(2,5-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT1A and 5-HT7 receptors and antidepressant-like properties. We performed the four plate test and the elevated plus maze test to determine anxiolytic-like activity. Toward a better understanding of the pharmacological properties of HBK-17 we used various functional assays to determine its intrinsic activity at 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors and UHPLC-MS/MS method to evaluate its pharmacokinetic profile. We observed the anxiolytic-like activity of HBK-17 in both behavioral tests and the effect was reversed by the pretreatment with WAY-100635, which proves that 5-HT1A receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D2, weakly 5-HT7 and very weakly 5-HT2A receptors. We demonstrated that HBK-17 preferentially activated s-arrestin signaling after binding to the 5-HT1A receptor. HBK-17 was rapidly absorbed after intraperitoneal administration and had a half-life of about 150 min. HBK-17 slightly penetrated the peripheral compartment and showed bioavailability of approximately 45%. The unique pharmacological profile of HBK-17 encourages further experiments to understand its mechanism of action fully.

Details

Language :
English
Database :
OpenAIRE
Journal :
Frontiers in Pharmacology, Frontiers in Pharmacology, Vol 9 (2018)
Accession number :
edsair.doi.dedup.....2bf36924e6e7dcfc9b2d2a0cf0874268