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 importantpharmacological parameter in the drug development process. Several studies have suggested that the lipophilicity of a molecule canplay an important role. To date, this aspect has been studied for several G protein-coupled receptors (GPCRs) ligands but not forthe 5-HT 7 receptor (5-HT 7R), a GPCR proposed as a valid therapeutic target in neurodevelopmental and neuropsychiatric disordersassociated with abnormal neuronal connectivity. In this study, we report on structure−kinetics relationships of a set ofarylpiperazine-based 5-HT7 R ligands. We found that it is not the overall lipophilicity of the molecule that influences drug−targetinteraction kinetics but rather the position of polar groups within the molecule. Next, we performed a combination of moleculardocking studies and molecular dynamics simulations to gain insights into structure−kinetics relationships. These studies did notsuggest specific contact patterns between the ligands and the receptor-binding site as determinants for compounds kinetics. Finally,we compared the abilities of two 5-HT 7R agonists with similar receptor-binding affinities and different residence times to stimulatethe 5-HT7 R-mediated neurite outgrowth in mouse neuronal primary cultures and found that the compounds induced the effect withdifferent timing. This study provides the first insights into the binding kinetics of arylpiperazine-based 5-HT 7R ligands that can behelpful to design new 5-HT7 R ligands with fine-tuning of the kinetic profile.