Back to Search
Start Over
HBK-17, a 5-HT1A receptor ligand with anxiolytic-like activity, preferentially activates ß-arrestin signaling
- 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.
- Subjects :
- 0301 basic medicine
Intrinsic activity
Stimulation
Pharmacology
\beta-arrestin signaling
03 medical and health sciences
0302 clinical medicine
anxiolytic-like
Dopamine receptor D2
medicine
Pharmacology (medical)
5-HT1A receptor
mouse models
Receptor
Original Research
Chemistry
lcsh:RM1-950
Ligand (biochemistry)
030104 developmental biology
lcsh:Therapeutics. Pharmacology
Mechanism of action
medicine.symptom
Signal transduction
pharmacokinetics
030217 neurology & neurosurgery
$5-HT_{1A}$ receptor
ß-arrestin signaling
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Frontiers in Pharmacology, Frontiers in Pharmacology, Vol 9 (2018)
- Accession number :
- edsair.doi.dedup.....2bf36924e6e7dcfc9b2d2a0cf0874268