S4B-3 Targeted to Serotonergic and Adenosine Systems in Parkinsons Disease Drug Development

摘要

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.