Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder. While dopaminergic agents are effective in reliving the motor symptoms, however, chronic dopamine replacement treatment  could also induce motor fluctuation and dyskinesia. In addition,  there is still a clinical unmet need for novel medications that can treat the non-motor symptoms.  Recent evidence suggests that the serotonergic nervous system may be an important target for both motor and non-motor symptoms for PD Meanwhile, adenosine A2A receptors enriched in basal ganglia areas and their antagonistic role towards dopamine receptor stimulation, have positioned A2A receptor antagonists as an a promising target to improve the motor deficits. We have developed a series of dual dopamine receptor and 5-HT1A receptor ligands and A2A receptor antagonists either through natural resource or rational design. We pharmacologically characterized those compounds and provided  clear evidences that dual 5-HT/dopamine or  A2A receptor antagonist exhibited excellent anti-Parkinsonian effect while  it reduced the development of dyskinesia and effectively relieved some of the non-motor symptoms  in PD animal models.