PLoS ONE (2018)
Update date:2022-08-28
Topics:
Shao, Yi-Ming
Ma, Xiaohua
Paira, Priyankar
Tan, Aaron
Herr, Deron Raymond
Lim, Kah Leong
Ng, Chee Hoe
Venkatesan, Gopalakrishnan
Klotz, Karl-Norbert
Federico, Stephanie
Spalluto, Giampiero
Cheong, Siew Lee
Chen, Yu Zong
Pastorin, Giorgia
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7–11.2 μM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5–40.2 μM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM), hepatotoxicity (up to 30 μM) or cardiotoxicity (up to 30 μM).
View MoreContact:852-27701081
Address:Room 2509, New Tech Plaza, 34 Tai Yau St., San Po Kong, HK
shandong zhongke taidou chemical co.,ltd
Contact:86-531-88682301
Address:Jinan shandong Province CHina
Xinji City Taida Sinopec Co., Ltd.
Contact:0086-311-85341278
Address:No.6, Nanhua Road,Xinji City Road,Hebei Province,China
SHAANXI TOP PHARM CHEMICAL CO.LTD
Contact:+86-029-85733403
Address:No.108 ,west sector,south er huan,xi'an,china
website:http://www.shengmaochem.com
Contact:86-27-82853423, 82819281
Address:Rm 202, A Unit Huaqiao Building No. 2, Lihuangpi Road, Wuhan, China
Doi:10.1039/c39950001489
(1995)Doi:10.3184/174751911X13026263307911
(2011)Doi:10.1081/SCC-200026654
(2004)Doi:10.1021/jp049334r
(2004)Doi:10.1021/ic901401t
(2009)Doi:10.1021/ja00078a084
(1993)