(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: Rui Zhao, Weijian Lu, Xing Fang, Lin Guo, Zhi Yang, Na Ye, Jiahao Zhao, Zhili Liu, Jia Jia, Longtai Zheng, Bin Zhao, Ao Zhang, Xuechu Zhen
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 124 Pg. 204-10 (Sep 2014) ISSN: 1873-5177 [Electronic] United States
• PMID: 24955866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 11-amino-N-propylnoraporphine
• Antiparkinson Agents
• Aporphines
• DNA Primers
• Dopamine Agonists
• Receptors, Dopamine D2
• Serotonin Receptor Agonists
• Receptor, Serotonin, 5-HT1A
• Levodopa
• Oxidopamine

Topics

• Animals
• Antiparkinson Agents (pharmacology, therapeutic use)
• Aporphines (pharmacology, therapeutic use)
• Base Sequence
• DNA Primers
• Disease Models, Animal
• Dopamine Agonists (pharmacology)
• Drug Interactions
• Dyskinesia, Drug-Induced (prevention & control)
• Levodopa (adverse effects, therapeutic use)
• Male
• Oxidopamine (toxicity)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (drug effects)
• Receptors, Dopamine D2 (agonists)
• Reverse Transcriptase Polymerase Chain Reaction
• Serotonin Receptor Agonists (pharmacology)