Molecular Design, Synthesis And Pharmacological Activity Studies Of D ₃ , 5-HT

Psychotic disease severely impairs human health. In the past decades, the pathology of schizophrenia and action mechanism of antipsychotics has been intensively studied. It is claimed that antipsychotics targeting dopamine D2receptor (D2R) can treat positive symptoms of schizophrenia but usually accompanies severe extrapyramidal symptoms side effects (EPS). Antipsychotics targeting dopamine D3receptor (D3R), serotonin5-HT1A and5-HT2A receptors (5-HT1AR,5-HT2AR) can effectively treat negative symptoms of schizophrenia and improve cognitive symptoms and mood disorders.Notably, they have no liability of EPS. Atypical antipsychotic which is potent antagonist for dopamine D2R and conbines with a serotonin5-HT2AR or D3R antagonistic activity, or with serotonin5-HT1AR agonistic activity can treat both negative and positive symptoms of schizophrenia. Since most antipsychotics have D2R occupany, they can hardly avoid EPS effect. So it is of great significance to exploit molecules with a multireceptor affinity profile but with a low or no affinity for D2R with the eventual aim to treat the complex multi-symptoms of schizophrenia and reduce EPS side effects.The improved "dynamic virtual screening" strategy, applying molecular dynamics simulation and conformational cluster analysis strategy, was used to obtain the flexible conformation of D3R and build dynamic pharmacophore model. Furthermore, the active sites were mapped by grid calculation and multiple dynamic D3R pharmacophore models were built. After validating the accuracy of the pharmacophore models, virtual screening was carried out on two available compound database:Spece and Maybridge. Finally,95candidates were purchased and some of them were proved to show multitarget profile. Compound HTS01687show moderate activities towards D3R、5-HT1AR、5-HT2AR and no activity to D2R. Hence, compound HTS01687was chosen as our lead compound to undergo structural modification with the aim to obtain novel potential multifunctional atypical antipsychotic agents targeting D3R, serotonin5-HT1AR and5-HT2AR.Based on the interaction modes of the lead with three receptors suggested by molecular docking, we conducted a two-round optimizationatthe Tail, Linker and Head moities. Totally,10seriesof derivatives characterized by indolpiperazie moiety were designed and synthesized. All of these compounds were evaluated in the pharmacological activities toward dopamine D1R, D2R, D3R and5-HT1AR and5-HT2AR in vitro.5of them were found to exhibitmixed activities toward D3R,5-HT1AR and5-HT2AR, indicating that they are potential novel antipsychotic agents.8of them were found to display dual activities toward5-HT1AR and5-HT2AR, and2selective5-HT2AR ligands and3selective D3R ligands were also identified. These selective ligands can be used as molecular probes to study physiological function and activation mechanism of receptors. Through a deep investigation into the interaction modes of these compounds with the receptors, we found that the introduction of hydrophobic groups on the amide moiety can enhance activities towards D3R、5-HT1AR and5-HT2AR-In addition, we explored the intrinsicfactor of highly selectivity towards D3R over D2R exhibited by the novel ligands reported herein, and found that the residue S182in ECL2may be the molecular determinant for the highly selectivity.Considering the low activity of the lead compound, the combination principle was emplyed to introduce the active group of the selective D3R ligands into the lead, generating a new serial of compounds bearing benzylpiperazine scaffold. Among the3categories of these derivatives,1was found to have mixed activity toward D3R,5-HT1AR and5-HT2AR, with a2-fold increase for D3R while maintaining5-TH1AR and5-HT2AR activities.L-Stepholidine (l-SPD), belonging to tetrahydroprotoberberines (THPBs), is an active ingredient of Chinese herb Stepania, itis the first compound found to have a dual function as a D1R agonist and D2R/D3R antagonist. Although it isa potential antipsychotics,l-SPD elicits EPS side effectsdue toits D2R activity. With the aim to reduce the EPS effect caused by D2R activity and enhance D1R activity, we introduce the active group of selective D1R into l-SPD to generate a serial of derivatives containing benzazepine moiety. Pharmacological tests show that two of them have activities over D1R and D3R, and one have selective D1R activity with a Ki value of3fold higher than l-SPD.