Details

Autor(en) / Beteiligte

• Pytka, Karolina
• Głuch-Lutwin, Monika
• Żmudzka, Elżbieta
• Sałaciak, Kinga
• Siwek, Agata
• Niemczyk, Katarzyna
• Walczak, Maria
• Smolik, Magdalena
• Olczyk, Adrian
• Gałuszka, Adam
• Śmieja, Jarosław
• Filipek, Barbara
• Sapa, Jacek
• Kołaczkowski, Marcin
• Pańczyk, Katarzyna
• Waszkielewicz, Anna
• Marona, Henryk

Titel

HBK-17, a 5-HT1A Receptor Ligand With Anxiolytic-Like Activity, Preferentially Activates ß-Arrestin Signaling

Ist Teil von

• Frontiers in pharmacology, 2018-10, Vol.9, p.1146-1146

Ort / Verlag

Frontiers Media S.A

Erscheinungsjahr

2018

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Numerous studies have proven that both stimulation and blockade of 5-HT 1A and the blockade of 5-HT 7 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-HT 1A and 5-HT 7 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-HT 1A , 5-HT 2A , 5-HT 7 , and D 2 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-HT 1A receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D 2 , weakly 5-HT 7 and very weakly 5-HT 2A receptors. We demonstrated that HBK-17 preferentially activated ß-arrestin signaling after binding to the 5-HT 1A 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.