title: (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.
abstract: 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-HT1A receptors may provide a novel approach for drug development in PD and LID.
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors: Rui
authors: R
authors: Zhao
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors: Weijian
authors: W
authors: Lu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors: Xing
authors: X
authors: Fang
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors: Lin
authors: L
authors: Guo
authors: Department of Neurology, Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong, China.
authors: Zhi
authors: Z
authors: Yang
authors: Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
authors: Na
authors: N
authors: Ye
authors: Department of Neurology, Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong, China.
authors: Jiahao
authors: J
authors: Zhao
authors: Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
authors: Zhili
authors: Z
authors: Liu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors: Jia
authors: J
authors: Jia
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors: Longtai
authors: L
authors: Zheng
authors: Department of Neurology, Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong, China.
authors: Bin
authors: B
authors: Zhao
authors: Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China. Electronic address: aozhang@mail.shcnc.ac.cn.
authors: Ao
authors: A
authors: Zhang
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Electronic address: zhenxuechu@suda.edu.cn.
authors: Xuechu
authors: X
authors: Zhen
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001060:Aporphines / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: C000597738:11-amino-N-propylnoraporphine; D000978:Antiparkinson Agents; D001060:Aporphines; D017931:DNA Primers; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; D016627:Oxidopamine
keywords: 5-HT(1A) receptor; Dopamine-D(2) receptor; L-DOPA-induced dyskinesia; Parkinson disease