Screening And Evaluation Of The Novel Potential Adenosine A_2A Receptor Antagonists

Object: Parkinson’s disease (Parkinson’s disease, PD) is a neurodegenerativedisorder of the central nervous system. Although the current drug therapy caneffectively relieve the movement symptom of the PD, the adverse effects are alsosignificant. Meanwhile, it produces little improvement on the patient’s mood, sleep andcognition. So it is need to discover new drug to improve life quality of the patients.Adenosine A2Areceptor antagonists (A2Areceptor antagonist) has become focus point innew drug discovery for PD, KW-6002is the first drug proved for clinical use in Japan in2013.In a joint effort with medicinal chemist, we have designed and synthesized a seriesof new compounds that are subjected to screen for A2Areceptor binding and functionalassays. Further we selected a few potent compounds to test their in vivo activity andmetabolic profiles. We identified three compounds that exhibited potent activity thatmay be promising lead for further study.Methods： Receptor binding of A2Areceptor were conducted in membranepreparations for stable expressed A1or A2Areceptors HEK-293cells, using radiolabeledligands. After initial screening, more than95%inhibition compounds elicited by assayswere subjected to IC50and Ki values. Last three collected compounds were tested onthe haloperidol-induced catalepsy and also for the metabolic profile.Results: We found that forty-one new compounds exhibited good affinity to A2Areceptor with95%inhibition. We further assayed the IC50and Ki value. Compoundswith IC50<15nM: AA041, AA042, AA051, AA039, AA043, AA070;15nM <IC50<100nM: AA044, AA035, AA062, AA054; compounds with100nM <IC50<150nM:AA038, AA045. The compounds AA041, AA042, AA051were able to reverse the phenomenon stiff obstacles caused by haloperidol in animal experiments.The AA041has the strongest effect among all tested compounds. Preliminary metabolic profileshowed that three compounds could cross the blood barrier and have high concertrationin strtriatum.Conclusion: Three potent novel A2Areceptor antagonists have been found, whichexhibited potential anti-LID activity with good brain exposure. The present studyprovides a promising new anti-PD drug candidate.