TY - JOUR
T1 - 6aR-11-Amino-N-propyl-noraporphine, a new dopamine D2 and serotonin 5-HT1A dual agonist, elicits potent antiparkinsonian action and attenuates levodopa-induced dyskinesia in a 6-OHDA-lesioned rat model of Parkinson's disease
AU - Zhao, Rui
AU - Lu, Weijian
AU - Fang, Xing
AU - Guo, Lin
AU - Yang, Zhi
AU - Ye, Na
AU - Zhao, Jiahao
AU - Liu, Zhili
AU - Jia, Jia
AU - Zheng, Longtai
AU - Zhao, Bin
AU - Zhang, Ao
AU - Zhen, Xuechu
N1 - Funding Information:
This work was financially supported by grants from the National Science Foundation of China ( 81130023 , 81125021 , 811373382 , 81100918 ) and the National Basic Research Plan (973) of the Ministry of Science and Technology of China ( 2009CB522000 , 2011CB5C4403 ). Support from the Priority Academic Program Development of Jiangsu Higher Education Institutes is also appreciated.
PY - 2014/9
Y1 - 2014/9
N2 - Parkinson's disease (PD) drug therapy remains a challenge. Dual modulation of dopamine and 5-HT receptors has emerged as a promising approach in anti-PD drug development. Taking advantage of the newly discovered aporphine analogue(s), (6aR)-11-amino-N-propyl-noraporphine (SOMCL-171), which exhibited dual D2/5-HT1A receptor agonistic activity, we studied the effects of the compound on levodopa-induced dyskinesia (LID) in a PD animal model. The results demonstrated that SOMCL-171 elicited a potent anti-PD effect in a 6-OHDA-lesioned rat model. Chronic use of SOMCL-171 reduced LID without compromising the antiparkinsonian efficacy. Furthermore, we found that the antidyskinesia effect of SOMCL-171 is associated with its 5-HT1A agonistic activity and the up-regulation of the striatal 5-HT1A receptor. The present data indicated that chronic SOMCL-171 alone produced potent antiparkinsonian effects with weak dyskinesia, compared with that of levodopa. In addition, chronic SOMCL-171 application attenuated the development of levodopa-induced LID at no expense to the antiparkinsonian efficacy. Taken together, our data suggested that dual modulation of D2/5-HT 1A receptors may provide a novel approach for drug development in PD and LID.
AB - Parkinson's disease (PD) drug therapy remains a challenge. Dual modulation of dopamine and 5-HT receptors has emerged as a promising approach in anti-PD drug development. Taking advantage of the newly discovered aporphine analogue(s), (6aR)-11-amino-N-propyl-noraporphine (SOMCL-171), which exhibited dual D2/5-HT1A receptor agonistic activity, we studied the effects of the compound on levodopa-induced dyskinesia (LID) in a PD animal model. The results demonstrated that SOMCL-171 elicited a potent anti-PD effect in a 6-OHDA-lesioned rat model. Chronic use of SOMCL-171 reduced LID without compromising the antiparkinsonian efficacy. Furthermore, we found that the antidyskinesia effect of SOMCL-171 is associated with its 5-HT1A agonistic activity and the up-regulation of the striatal 5-HT1A receptor. The present data indicated that chronic SOMCL-171 alone produced potent antiparkinsonian effects with weak dyskinesia, compared with that of levodopa. In addition, chronic SOMCL-171 application attenuated the development of levodopa-induced LID at no expense to the antiparkinsonian efficacy. Taken together, our data suggested that dual modulation of D2/5-HT 1A receptors may provide a novel approach for drug development in PD and LID.
KW - L-DOPA-induced dyskinesia
KW - Parkinson disease
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U2 - 10.1016/j.pbb.2014.06.011
DO - 10.1016/j.pbb.2014.06.011
M3 - Article
C2 - 24955866
AN - SCOPUS:84903846715
SN - 0091-3057
VL - 124
SP - 204
EP - 210
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
ER -