(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

Zhao, Rui; Lu, Weijian; Fang, Xing; Guo, Lin; Yang, Zhenjie; Ye, Na; Zhao, Jiahao; Liu, Zhili; Jia, Jia; Zheng, Longtai; Zhao, Bin; Zhang, Ao; Zhen, Xuechu

doi:10.1016/j.pbb.2014.06.011

Cited by 24 publications

(14 citation statements)

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“…Although the precise pathogenic mechanism leading to neurodegeneration in PD is unknown, it is widely accepted that neuroinflammation, oxidative stress (OS) and mitochondrial dysfunction may contribute to dopaminergic neuron damage [3][4][5][6][7] . In addition to dopamine replacement therapy, such as levodopa, in past decades, tremendous efforts have been made to develop new therapeu-tic agents for PD, including selective dopamine receptor agonists, A 2A receptor antagonists and dual dopamine/serotonin receptor agonists [8][9][10][11][12] . However, these drugs can relieve only the symptoms of PD and are not a cure.…”

Section: Introductionmentioning

confidence: 99%

Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity

et al. 2016

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Section: Introductionmentioning

confidence: 99%

Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity

et al. 2016

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“…10,[16][17][18] Recent findings showed that the 5-HT 1A R agonists could be the potential treatments for ischemic stroke. 4,9,19 Medicines like buspirone, gepirone, tandospirone and vilazodone that act as 5-HT 1A R partial agonists have been used for years as anxiolytics or antidepressants. 1,2,20 The reported new 5-HT 1A R ligands, F-15599, which showed potent antidepressant activity, and F13640 as a potential treatment of chronic pain, have entered clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Higher-Affinity Agonists of 5-HT_1AR Discovered through Tuning the Binding-Site Flexibility

Lian

Geng

et al. 2015

J. Chem. Inf. Model.

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Discovery of high-affinity and high-selectivity agonists of 5-HT1AR has become very attractive due to their potential therapeutic effects on multiple 5-HT1AR-related psychological and neurological problems. On the basis of our previously designed lead compound FW01 (Ki = 51.9 nM, denoted as 9a in the present study), we performed large-scale molecular dynamics simulations and molecular docking operations on 5-HT1AR-9a binding. We found the flip-packing events for the headgroup of 9a, and we also found that its tail group could bind flexibly at the agonist-binding site of 5-HT1AR. By finely tuning the flip-packing phenomenon of the 9a headgroup and tuning the binding flexibility of 9a tail group, we virtually designed a series of new 9a derivatives through molecular docking operations and first-principles calculations and predicted that these newly designed 9a derivatives should be higher-affinity agonists of 5-HT1AR. The computational predictions on the new 9a derivatives have been confirmed by our wet-experimental studies as chemical synthesis, binding affinity assays, and agonistic-function assays. The consistency between our computational design and wet-experimental measurements has led to our discovery of higher-affinity agonists of 5-HT1AR, with ∼50-fold increase in receptor-binding affinity and ∼25-fold improvements in agonistic function. In addition, our newly designed 5-HT1AR agonists showed very high selectivity of 5-HT1AR over subtype 5-HT2AR and also over three subtypes of dopamine receptors (D1, D2, and D3).

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“…1–6 Moreover, in the central nervous system (CNS), aporphines have been investigated as acetylcholinesterase inhibitors 7,8 and as ligands for serotonin, adrenergic and dopamine receptors. 9–14 …”

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confidence: 99%

C4 phenyl aporphines with selective h5-HT2B receptor affinity

Kapadia

Harding

2015

Bioorganic & Medicinal Chemistry Letters

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A group of aporphine alkaloids related to (±)-nantenine (1) and bearing a C4 phenyl and various C1 or N-substituents, was synthesized and evaluated for affinity to h5-HT receptors. In general, unlike nantenine, the analogues lack affinity for the h5-HT2A receptor and other 5-HT receptors but bind selectively to the h5-HT2B receptor. With regards to 5-HT2B affinity, there appears to be a low tolerance for bulky C1 or N-substituents when the C4 phenyl moiety is present. Compound 5a had the highest 5-HT2B affinity of the compounds tested, was found to be an antagonist and is selective vs other CNS receptors.

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(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

Cited by 24 publications

References 21 publications

Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity

Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity

Higher-Affinity Agonists of 5-HT_1AR Discovered through Tuning the Binding-Site Flexibility

C4 phenyl aporphines with selective h5-HT2B receptor affinity

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(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

Cited by 24 publications

References 21 publications

Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity

Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity

Higher-Affinity Agonists of 5-HT1AR Discovered through Tuning the Binding-Site Flexibility

C4 phenyl aporphines with selective h5-HT2B receptor affinity

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Product

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Higher-Affinity Agonists of 5-HT_1AR Discovered through Tuning the Binding-Site Flexibility