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Identification and optimization of a potent and highly selective D3 dopamine receptor agonist

中国药理学与毒理学杂志 2017年第10期31卷 950-951页

作者： Amy E MORITZ R Benjamin FREE Warren WEINER Muzna BACHANI Trevor DOYLE Noel SOUTHALL Marc FERRER Jonathan A JAVITCH Joseph STEINER Ara ABRAMYAN Lei SHI Jeffrey AUBé Kevin FRANKOWSKI David R SIBLEY Molecular Neuropharmacology Section National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 University of North Carolina Chapel Hill NC27599 Neurotherapeutic Development Unit National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 National Center for Advancing Translational Sciences Rockville MD 20892 Columbia University New York NY 10032 Computational Chemistry and Molecular Biophysics Unit Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse National Institutes of Health Baltimore MD 21224

OBJECTIVE dopamine receptors(DRs) are involved in the development and treatment of many neuropsychiatric *** available dopaminergic drugs modulate both DRD2 and DRD3,leading to side effects and uncertainty as to the roles each DR subtype plays *** lab employed high throughput screening paradigms to discover highly selective modulators for the *** The NIH Molecular Libraries Program 400,000 + small molecule library was screened using the Discove Rx Path Hunter?β-arrestin assay for compounds that activate the DRD3 without effects on the *** and counter-screens assessed selectivity and mechanisms of *** identified 62 potential agonists,and chose the most promising to perform a structure-activity relationship(SAR) study to increase potency while maintaining *** lead compound identified through this process,ML417,was also characterized using bioluminescence resonance energy transfer(BRET)-based β-arrestin recruitment and G-protein activation assays as well as p-ERK *** neuroprotective properties of this compound were assessed using a SHSY5 Y neuronal cell *** ML417 displays potent,DRD3-selective agonist activity in multiple functional *** and functional GPCR screens(>165 receptors) show ML417 has limited cross-reactivity with other ***417 also displays superior(compared to the reference compound pramipexole),dose-dependent protection against a decrease in neurite length induced by 10 μmol·L^(-1) of the neurotoxin,6-hydroxydopamine,in the SHSY5 Y cell *** We have discovered and characterized ML417,a potent and highly selective DRD3 *** compound will be useful as a research tool,and may prove useful as a therapeutic drug lead.

关键词： dopamine receptor high throughput screening subtype selectivity neuroprotection

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Regulation of the D2 dopamine receptor function by PSD-95

Regulation of the D2 dopamine receptor function by PSD-95

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Xuetao CHEN,Guozhang JIN,Xuechu ZHEN State Key Laboratory of Drug Research and Department of Pharmacology,Shanghai Institute of Materia Medica, Chinese Academy of Sciences,Shanghai 201203,China.

D dopamine receptors(DARs) is member of G protein coupled receptors(GPCR) family,coupled to G protein to inhibit AC activity and reduce the level of *** is one of the most validated targets in treatment and drug development of central nervous system(CNS) ***-95,an abundant component of the post-synaptic density(PSD),belongs to membrane associated guanylate kinase(MAGUK).PSD-95 not only acts as an anchor protein,but also plays an important role in functional ***,PSD-95 can interact with receptors,ion channels and recruit cytoplasmic signaling molecules to form signaling *** performed immunoprecipitation (IP) assay and the results indicated that PSD-95 interacted with DDAR through PSD-95 *** agonist activation,the association between PSD-95 and DDAR obviously ***-receptor binding experiments suggest that PSD-95 has no effect on the expression and binding property of DDAR,and PSD-95 did not affect the internalization and recovery of *** assay indicated that PSD-95 did not influence the inhibition of cAMP mediated by ***,we found that PSD-95 did not change the normal state of DDAR coupled G protein but accelerated the desensitization process and depress the efficiency of *** and PSD- 95 play a significant role in the development and treatment of *** study showed that the total level of PSD-95 decreased and the redistribution of PSD-95 in PSD reduced in 6-OHDA-lesioned rat model of ***, with chronic L-DOPA treatment,these level back to normal ***,the association between PSD-95 and DDAR decreased in PD rat,and back to normal level with chronic L-DOPA *** summary,PSD-95 and DDAR interacted with each other through PSD-95 *** total level,redistribution and the association with DDAR of PSD-95 changed in PD and L-DOPA induced dyskinesia(LID).The effect of PSD-95 on DDAR desensitization and resensitization was ***

关键词： dopamine receptor G protein coupled receptor D2DAR desensitization resensitization

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A Novel regulatory mechanism for D1 dopamine receptor function:role of PSD-95

A Novel regulatory mechanism for D1 dopamine receptor functi...

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中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Pei-Hua SUN,Jing-Ru WANG,Wei-Hua GU,Jie ZHENG~1,Guo-Zhang JIN,Xue-Chu ZHEN State key Laboratory for Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203 1 Department of Physiology and Membrane Biology,University of California at Davis School of Medicine,USA

＜正＞PSD-95 is enriched in the postsynaptic density which has been shown to play an important role in the regulation of neurotransmitter receptor *** direct physical interaction between PSD-95 and NMDA receptor was reported to regulate NMDA receptor traffic and *** employing either immunoprecipitation or fluorescence resonance energy transfer（FRET）,We found that PSD-95 is physically associated with D1 receptor in HEK cells which were cotransfected PSD-95 and D1 dopamine *** is true in brain *** of D1 receptor with selective agonist in PSD-95 and D1 receptor expressing cells enhanced the association between the two molecules in a timedependent *** assay indicates that agonist-stimulated cAMP was not altered by co-transfected with D1 receptor and PSD-95 as compared to cells that expressed D1 receptor only,indicating that PSD-95 does not alter D1 receptor-Gs protein ***,co-expression of PSD-95 also did not significantly alter the receptor ***,PSD-95 significantly accelerated the resensitization of D1Rs *** an effort to identify the interactive site,different constructs for encoding different PSD-95 domains were *** was found the PDZ containing domain of PSD-95 is critical for the D1 -PSD-95 interaction since cells transfected with PDZ domain was able to mimic the regulatory effect of PSD-95 on D1 receptor,removal of the PDZ domain,the PSD-95 failed to interact with D1 receptor. Taken together,the present data reveals a novel mechanism for D1 receptor functional ***-95 regulates D1 receptor resensitization by physical association with the D1 *** finding for PSD-95 accelerates the resensitization of D1 receptor may provided a mechanism for rapidly recruiting neurotransmitter receptor in peri-synsptic area which is critical for quick response to pulsate release of the neurotransmitters in any given time.

关键词： dopamine receptor internalization anchor protein desensitization

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Functional Magnetic Resonance Imaging Studies on dopamine receptor in Awake Normal and Parkinsonian Rhesus Monkeys

Functional Magnetic Resonance Imaging Studies on Dopamine Re...

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首届全国功能神经影像学和神经信息学研讨会

作者： Anders Andersen Peter Hardy Don Gash Department of Anatomy ＆ Neurobiology Morris K. Udall Parkinson Disease Research Center of Excellence Magnetic Resonance Imaging and Spectroscopy Center College of Medicine University of Kentucky Lexington KY 40536 4. Shandong University College of Medicine Jinan 250012 China. ) Department of Anatomy ＆ Neurobiology

＜正＞ Functional magnetic resonance imaging （fMRI） is increasingly recognized as being a non-invasive way to perform pharmacological investigations in experimental animal models and patients with neurotransmitter deficits such as in Parkinson’s disease （PD）. Previously, we have demonstrated in normal rhesus monkeys that pharmacological MRI （phMRI, i. e. functional MRI using drugs to evoke CNS responses） can be used to map age-associated changes in the nigrostriatal system following dopaminergic stimulation （NeuroImage 14: 1159 ?1167, 2001）. In the present study, phMRI was used to map dopamine （DA） receptor-mediated neuronal activity, specifically the D1 and D2 receptors in the basal ganglia of hemiparkinsonian rhesus monkeys. Twelve female rhesus monkeys rendered hemiparkinsonian via unilateral infusion of MPTP into the right carotid artery were used in this study. Three sec and age-matched normal controls were used for comparison. Apomor-phine, a mixed D1/D2 receptor agonist, evoked strong activations seen in the MPTP-lesoned putamen and substantia nigra. In parallel, a significant increase in movement speed was seen in these animals, as quantified using an automated video -tracking system. In normal monkeys, apomorphine evoked a small deactivation in the putamen, while no changes were seen in the SN. Accordingly, motor speed remained unchanged compared to baseline levels, in response to apomorphine challenge. Results suggest that phMRI is capable to detect MPTP-induced changes in the basal ganglia with dopaminergic stimulation and also prove that phMRI may be a potential powerful tool for Parkinson’s disease research in human.

关键词： Functional magnetic resonance imaging dopamine receptor Parkinson disease Monkey

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AB007. Visual signals modulate refractive error development through dopamine receptor signaling

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Annals of Eye Science 2017年第1期 361-361页

作者： Xiangtian Zhou School of Ophthalmology and Optometry Wenzhou Medical UniversityWenzhouChina

Myopia prevalence is dramatically increasing in recent years and in cases in which the refractive error is greater than −6.00 D this disease can lead to severe visual impairment as well as even blindness. Changes in visual input affect the balance between ocular growth and refractive power development. If a mismatch occurs during eye development, the severity of this error affects the degree of myopia. In different animal models of this disease, we found that spatial visual stimuli are essential for maintaining a stable refractive status and normal vision. This is evident because the effects of changes in temporal visual stimuli (e.g., flickering light) on this process depend on whether spatial information is present or absent in the visual environment. Furthermore, the frequency, wavelength and intensity of light are involved in controlling refraction development. However, the molecular mechanisms underlying light-induced refraction changes are still unclear. There is definitive evidence that dopamine (DA) is one of the regulators of this process. This retinal neurotransmitter released by dopaminergic amacrine cells appears to play an important role in vision-guided eye growth because its synthesis and release are positively associated with the light intensity and spatial stimuli impinging on the retina. We found that bright light enhances retinal DA synthesis, and attenuates form deprivation myopia (FDM) development via activation of the dopamine receptor 1 (D1R). A nonselective DA receptor agonist apomorphine (APO) inhibited FDM in dopamine receptor 2 (D2R) knockout mice. These individual similar effects of DA and APO in wildtype and D2R knockout mice suggest that D1R activation has a protective effect against myopia development. On the other hand, D2R activation instead appears to promote myopia development because either genetic D2R ablation or pharmacological inactivation of D2R also attenuates myopia development. Based on these results, we hypothesize that th

关键词： Myopia dopamine(DA) dopamine receptor visual stimuli

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dopamine in the prefrontal cortex plays multiple roles in the executive function of patients with Parkinson's disease

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Neural Regeneration Research 2024年第8期19卷 1759-1767页

作者： Zihang Zhou Yalong Yan Heng Gu Ruiao Sun Zihan Liao Ke Xue Chuanxi Tang Department of Neurobiology Xuzhou Key Laboratory of NeurobiologyXuzhou Medical UniversityXuzhouJiangsu ProvinceChina

Parkinson’s disease can affect not only motor functions but also cognitive abilities,leading to cognitive *** common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive *** functions help us plan,organize,and control our actions based on our *** brain area responsible for executive functions is called the prefrontal co *** acts as the command center for the brain,especially when it comes to regulating executive *** role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called ***,little is known about how dopamine affects the cognitive functions of patients with Parkinson’s *** this article,the authors review the latest research on this *** start by looking at how the dopaminergic syste m,is alte red in Parkinson’s disease with executive ***,they explore how these changes in dopamine impact the synaptic structure,electrical activity,and connection components of the prefrontal *** authors also summarize the relationship between Parkinson’s disease and dopamine-related cognitive *** information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson’s disease.

关键词： dopamine dopamine receptor dopamine transporter executive dysfunction neural network neural oscillation prefrontal cortex synaptic plasticity

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dopamine enhances duodenal epithelial permeability via the dopamine D5 receptor in rodent

Dopamine enhances duodenal epithelial permeability via the d...

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中国生理学会消化与营养专业委员会成立大会暨第一届学术会...

作者： Xiao-Yan FENG Dong-Ni ZHANG Yi-An WANG 朱进霞 Department of Physiology and Pathophysiology School of Basic Medical Science Capital Medical University 首都医科大学生理与病理生理学系

Objective The intestinal barrier is made up of epithelial cells and intercellular junctional complexes to regulate epithelial ion transport and ***(DA)is able to promote duodenal epithelial ion transport through D1-like receptors which includes subtypes of D(DR)and D(DR)but whether D1-like receptors are involved in the regulation of duodenal epithelial permeability is ***:FITC-dextran permeability short-circuit current(I)western blot immunohistochemistry and ELISA were used in human DR transgenic mice and hyper-endogenous enteric DA(HEnD)rats in this ***:DA induced a downward deflection in Iand an increase in FITC-dextran permeability which were inhibited by the D1-like receptor antagonist *** DA decreased duodenal transepithelial resistance(TER)an effect also reversed by SCH-23390.A strong immunofluorescence signal for DR but not DR was observed in rat *** human DR knock-in transgenic mice duodenal mucosa displayed an increased basal Iwith high FITC-dextran permeability and decreased TER with a lowered expression of tight junction proteins suggesting attenuated duodenal barrier function in these transgenic *** knock-down transgenic mice manifested a decreased basal Iwith lowered FITC-dextran *** an increased FITC-dextran permeability combined with decreased TER and tight junction protein expression in duodenal mucosa were also observed in HEnD ***:This study demonstrates for the first time that DA enhances duodenal epithelial permeability via DR which provides new experimental and theoretical evidence for the regulation of DA on duodenal epithelial barrier function.

关键词： dopamine dopamine receptor Duodenum Epithelial permeability

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Dissociable role of dopamine D1 and D2 receptor in the impulsive choice of naive rats and cocaine treated rats

Dissociable role of dopamine D1 and D2 receptor in the impul...

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中国神经科学学会第十届全国学术会议

作者： Yan-Fang ZUO Yi-Jing LI Peng YU Xin-Sheng WANG Xing-Jie PING Cai-Lian CUI Neuroscience Research Institute ＆ Department of Neurobiology School of Basic Medical SciencesPeking University Key Laboratory for Neuroscience Ministry of Education /National Health and Family Planning CommissionPeking University

Objective Studies has showed that impulsivity is tightly linked to drag *** and drag-experienced animals have decision-making deficits in delayed reinforcement choice task,in which they prefer small immediate rewards over large delayed *** system within the amygdala-striatal circuit is believed to be the point of convergence for impulsive choice and *** the exact mechanism of DA in impulsive choice is still *** Delay discounting model was performed to measure impulsive choice in ***（1） Rats in control group preferred the large reward when its delivery was immediate,and shifted their preference to the small reward gradually as the delay to the large reward was *** cocaine（10,15 or 20mg/kg） treated rats chose the large delayed reward more often than the saline treated rats,demonstrating that acute cocaine exposure could decrease the impulsive choice.（2） Before cocaine treatment,D1 receptor antagonist SCH23390（0.01,0.02 mg/kg,i.p.） could dose dependently increase the impulsive choice but had no effect on the inhibition of impulsive choice caused by cocaine *** pre-injection of D2 receptor antagonist eticlopride（0.06 mg/kg,i.p.）could reverse the reduced impulsive choice without altering the delay dependent choice behavior in naive rats.（3）Microinjection of D1 receptor antagonist SCH23390（1 μg/side） into the NAc core and the BLA could increase the impulsive choice.（4） Infusions of the dopamine D2 receptor antagonist eticlopride into the BLA but not the NAc core completely blocked the inhibitory effects of acute cocaine on impulsive *** These data demonstrated a dissociable role of the dopamine D1 and D2 receptors in the impulsive choice of naive rats and acute cocaine treated *** prefer to delay rewards in naive rats depended on dopamine D1 receptors in BLA and NAc core,while the activation of D2 receptors in BLA mediated the inhibition effect of acute cocaine on impuls

关键词： dopamine receptor impulsive choice cocaine

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Effect of PDⅠAdministration on dopamine receptors mRNAs Expression in the Lesioned Striatum of PD Rat Model

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2005年第6期25卷 645-647页

作者：杨梅孙圣刚曹学兵 Department of Neurology Union Hospital Tongji Medical College Huzhong University of Science and Technology Wuhan 430022 China

To study the effect of PD Ⅰ administration on dopamine receptors （DR, , DRz ） mRNAs expression in the lesioned striatum of the PD rat model and confirm if PDⅠ has the effect of dopamine receptor agonist. The PD rats with unilateral 6-hydroxydopamine lesioned were administrated with PD Ⅰ , L-dopa methyl/benserazide, L-dopa methyl/benserazide/ PD Ⅰ , normal saline respectively for 4 weeks and their behavioral changes were observed. Then the rats were sacrificed and RT-PCR technique was used to detect changes of dopamine receptors （DR1, DR2） mRNAs expression in the ipsilateral striatum 1 day after the last treatment. The results showed that treatment with PD Ⅰ plus L-dopa resulted in a stable contralateral rotation behavior; treatment with L-dopa resulted in a progressively increased contralateral rotation behavior. Rotation behavior induced by anhydromorphine decreased with PD Ⅰ or PD Ⅰ plus L-dopa treatment. Treatment With L-dopa or PD Ⅰ plus L-dopa, up-regulation of DR, mRNA and down-regulation of DR2 mRNA were observed in the ipsilateral striatum which were more obvious than that treated with PD Ⅰ or vehicle （P〈0. 05）. It was concluded that long-term treatment with PD Ⅰ could alleviate the behavior of PD rats. PD Ⅰ had no apparent effect on the dopamine receptors （DRI , DRz ） mRNAs expression in the ipsilateral striatum and the PD Ⅰ has no agonist effect on dopamine receptors.

关键词： Parkinson's disease 6-hydroxydopamine dopamine receptor

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D2- like but not D1- like dopamine receptors in ventrolateral orbital cortex are involved in apomorphine-induced antiallodynia in a neuropathic pain model of rats

D2- like but not D1- like dopamine receptors in ventrolatera...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Yong-Hui DANG~1,Yan ZHAO~1,Bo XING~1,Xiao-Jie ZHAO~1,Teng CHEN~1,Jing-Shi TANG~2,Fu-Quan HUO~2,Feng-Yi XU~2, Chao-LingQU~(2,*) 1 Department of Forensic Medicine,Key Laboratory of Environment and Gene Related to Diseases,Ministry of Education, Xi''an Jiaotong University School of Medicine,Xi''an 710061,China 2 Department of Physiology and Pathophysiology,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education,Xi''an Jiaotong University School of Medicine,Xi''an 710061,China

＜正＞Objective The ventrolateral orbital cortex（VLO） is part of an endogenous analgesic system consisting of an ascending pathway from the spinal cord to VLO via the thalamic nucleus submedius（Sm） and a descending pathway to the spinal cord relaying in the periaqueductal gray（PAG）.The aim of the present study was to examine whether dopamine and its receptors are involved in the antinociception in *** The animal model of persistent peripheral neuropathic pain-spared nerve injury（SNI） was *** withdrawal threshold in response to von-Frey hair stimulation of the injury side hindpaw was measured as an index of mechanical ***（1） Microinjection of the nonselective dopamine receptor agonist apomorphine（1.0,2.5,5.0μg in 0.5μl） into the VLO significantly increased the paw withdrawal threshold in a dose-dependent manner,which was reversed by pretreatment with selective D2-like dopamine receptor antagonist raclopride（1.5μg in 0.5μl）,but not selective D1-like dopamine receptor antagonist（SCH23390 5.0μg in 0.5μl）.（2） Microinjection of raclopride or SCH23390 alone into the VLO had no effects on mechanical paw withdrawal threshold. Conclusion The results suggest that dopamine neurotransmitter is involved in VLO-induced anti-allodynia,and this effect is mediated by D2-like but not Dl-like dopamine receptors.

关键词： ventrolateral orbital cortex dopamine receptor raclopride SCH23390 mechanical allodynia spared nerve injury rat

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