In Vitro and In Silico Analysis of the Residence Time of Serotonin 5‑HT₇ Receptor Ligands with Arylpiperazine Structure: A Structure–Kinetics Relationship Study

During the last decade, the kinetics of drug–target interaction has received increasing attention as an important pharmacological parameter in the drug development process. Several studies have suggested that the lipophilicity of a molecule can play an important role. To date, this aspect has been studied for several G protein-coupled receptors (GPCRs) ligands but not for the 5-HT₇ receptor (5-HT₇R), a GPCR proposed as a valid therapeutic target in neurodevelopmental and neuropsychiatric disorders associated with abnormal neuronal connectivity. In this study, we report on structure–kinetics relationships of a set of arylpiperazine-based 5-HT₇R ligands. We found that it is not the overall lipophilicity of the molecule that influences drug–target interaction kinetics but rather the position of polar groups within the molecule. Next, we performed a combination of molecular docking studies and molecular dynamics simulations to gain insights into structure–kinetics relationships. These studies did not suggest specific contact patterns between the ligands and the receptor-binding site as determinants for compounds kinetics. Finally, we compared the abilities of two 5-HT₇R agonists with similar receptor-binding affinities and different residence times to stimulate the 5-HT₇R-mediated neurite outgrowth in mouse neuronal primary cultures and found that the compounds induced the effect with different timing. This study provides the first insights into the binding kinetics of arylpiperazine-based 5-HT₇R ligands that can be helpful to design new 5-HT₇R ligands with fine-tuning of the kinetic profile.