HBK-17, a 5-HT(1A) Receptor Ligand With Anxiolytic-Like Activity, Preferentially Activates ß-Arrestin Signaling

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.