Molecular Design, Synthesis And Pharmacological Study On Novel Anti-Parkinson’s Agents Led By L-Stepholidine

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder with the symptoms of shaking, rigidity, slowness of movement and postural instability. There are up to17.2million PD patients in China, and the morbidity in people above55years old has reached to1%. Besides the high morbidity of PD, it’s a lifelong disease which brings heavy burden to the family and society. Although there are many treatments, long-acting drugs with low side effects haven’t been available, and there isn’t effective method for neuroprotection and neurorestoration. Therefore, it’s an important direction for discovery of new generation of anti-Parkinson’agents to develop drugs with specific action mechanism for personalized therapy and reducing severe side effects caused by long-term medication. Recent studies reveal that D1agonists and D3agonists play important roles in treating PD, with higher efficiency and lower side effects compared to D2agonists. D3antagonists are also useful for anti-PD as adjuvant therapy.L-Stepholidine (l-SPD) is a novel extract of Chinese herb Stepania with dopamine D1receptor agonistic, D2receptor antagonistic and D3receptor antagonistic multiple actions, which belongs to tetrahydroprotoberberines (THPBs). In spite of novel action, its clinical use is limited by the low bioavailability led by its poor solubility in both water and lipid. And its D2receptor antagonistic action limits its use in anti-PD. We took SPD as lead compound to replace its ring-D for the drug-like2-aminothiazole ring lent from the D3agonist pramipexole in the light of bioisosterism based on the interaction mode of l-SPD with D1receptor, with the aim to maintain its D1agonistic activity and obtain D3agonistic activity and further improve the solubility in water or lipid for better bioavailability. Meanwhile, we changed the substitents on A and D rings to explore better substitution mode. Finally,17compounds were synthesized. Their water solubility all improved compared with SPD. Competitive binding assays showed that four active compounds exhibited moderate to good D1activities, one of which even has D3activity. And different from l-SPD, they lose the D2activity, which isn’t required in anti-PD. All the active compounds have3-methoxyl and2-hydroxyl groups at A ring. Then we explored the interaction modes between the active molecules and D1receptor with a agonistic conformation through molecular docking, which indicated that the interaction retained the conserved binding mode:The conserved D3.32formed salt-bridge with the protonated nitrogen of our active compounds, the S5.42and S5.46formed stable hydrongen bonds with the oxygen of A ring, and different from SPD, the S188in EL-2formed hydrongen bond with the nitrogen in D ring, which may play an important role in their selective activity for D1receptor. The docking results suggested that these molecules were probably D1agonists, which was to be verified by function assays. The interaction modes between the molecule with dual activities and the D3receptor would be explored according to the results of function assays.In addition to the above-mentioned work, we discovered a5-HT2A inhibitor through virtual screening based on pharmacophore model. In view of5-HT2A receptor antagonists’role in relieving motor symptoms of PD and dyskinesia caused by long-term use of L-DOPA, a method by integrating a set of computational approaches and experiments:protein structure prediction, pharmacophore-based virtual screening, automated molecular docking and pharmacological bioassay was built to discover novel5-HT2A inhibitors. Finally, a5-HT2A inhibitor with Ki value of593.89±34.10nM was found.