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

• Published in: Frontiers in pharmacology Vol. 9; p. 1146
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 16-10-2018
• Subjects: 5-HT1A receptor; anxiolytic-like; mouse models; pharmacokinetics; Pharmacology; ß-arrestin signaling
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2018.01146

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.