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Dopamine D2

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https://www.readbyqxmd.com/read/29352161/the-action-of-a-negative-allosteric-modulator-at-the-dopamine-d2-receptor-is-dependent-upon-sodium-ions
#1
Christopher J Draper-Joyce, Ravi Kumar Verma, Mayako Michino, Jeremy Shonberg, Anitha Kopinathan, Carmen Klein Herenbrink, Peter J Scammells, Ben Capuano, Ara M Abramyan, David M Thal, Jonathan A Javitch, Arthur Christopoulos, Lei Shi, J Robert Lane
Sodium ions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D2 receptor (D2R). Experimental and computational evidences have revealed that this effect is mediated by the binding of Na+ to a conserved site located beneath the orthosteric binding site (OBS). SB269652 acts as a negative allosteric modulator (NAM) of the D2R that adopts an extended bitopic pose, in which the tetrahydroisoquinoline moiety interacts with the OBS and the indole-2-carboxamide moiety occupies a secondary binding pocket (SBP)...
January 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348266/dopamine-receptor-agonist-treatment-for-idiopathic-dystonia-a-reappraisal-in-humans-and-mice
#2
Xueliang Fan, Yuping Donsante, H A Jinnah, Ellen J Hess
Although dystonia is often associated with abnormal dopamine neurotransmission, dopaminergic drugs are not currently used to treat dystonia because there is a general view that dopaminergic drugs are ineffective. However, there is little conclusive evidence to support or refute this assumption. Therefore, to assess the therapeutic potential of these compounds, we analyzed results from multiple trials of dopamine receptor agonists in patients with idiopathic dystonias and also tested the efficacy of dopamine receptor agonists in a mouse model of generalized dystonia...
January 18, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29346639/comparison-of-dopamine-d3-and-d2-receptor-occupancies-by-a-single-dose-of-blonanserin-in-healthy-subjects-a-positron-emission-tomography-study-with-11c-phno
#3
Amane Tateno, Takeshi Sakayori, Woo-Chan Kim, Kazuyoshi Honjo, Haruo Nakayama, Ryosuke Arakawa, Yoshiro Okubo
Background: Blockade of D3 receptor, a member of the dopamine D2-like receptor family, has been suggested as a possible medication for schizophrenia. Blonanserin has high affinity in vitro for D3 as well as D2 receptors. We investigated whether a single dose of 12 mg blonanserin, which was within the daily clinical dose range (i.e., 8-24 mg) for the treatment of schizophrenia, occupies D3 as well as D2 receptors in healthy subjects. Methods: Six healthy males (mean 35...
January 13, 2018: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29346545/influence-of-nicotine-metabolism-ratio-on-11c-phno-pet-binding-in-tobacco-smokers
#4
Patricia Di Ciano, Rachel F Tyndale, Esmaeil Mansouri, Christian S Hendershot, Alan A Wilson, Dina Lagzdins, Sylvain Houle, Isabelle Boileau, Bernard Le Foll
Background: Identifying the biological basis of smoking cessation success is of growing interest. The rate of nicotine metabolism, measured by the nicotine metabolite ratio (NMR), affects multiple aspects of nicotine dependence. Fast nicotine metabolizers (FM) tend to smoke more, experience more withdrawal and craving and have lower cessation rates as compared to slow metabolizers (SM). The NMR predicts treatment response, and differences in brain activation between FM and SM have been reported in fMRI studies...
January 13, 2018: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29339486/cell-type-specific-role-for-nucleus-accumbens-neuroligin-2-in-depression-and-stress-susceptibility
#5
Mitra Heshmati, Hossein Aleyasin, Caroline Menard, Daniel J Christoffel, Meghan E Flanigan, Madeline L Pfau, Georgia E Hodes, Ashley E Lepack, Lucy K Bicks, Aki Takahashi, Ramesh Chandra, Gustavo Turecki, Mary Kay Lobo, Ian Maze, Sam A Golden, Scott J Russo
Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29339293/methylphenidate-significantly-alters-the-functional-coupling-between-the-prefrontal-cortex-and-dopamine-neurons-in-the-ventral-tegmental-area
#6
Ike C Dela Peña, Guofang Shen, Wei-Xing Shi
Amphetamine-like psychostimulants, including methylphenidate, have been shown to produce two opposing effects on dopamine (DA) neurons: a DA receptor-mediated feedback inhibition and a non-DA receptor-mediated excitation. To test whether the latter effect is mediated through the prefrontal cortex (PFC), we made dual-site recordings from the PFC and ventral tegmental area (VTA). Consistent with previous reports, methylphenidate inhibited VTA DA neurons. The D2 receptor antagonist raclopride completely reversed the inhibition and further increased the activity, particularly bursting, to above pre-drug baseline...
January 12, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29337986/the-e2-65a-mutation-disrupts-dynamic-binding-poses-of-sb269652-at-the-dopamine-d2-and-d3-receptors
#7
Ravi Kumar Verma, Ara M Abramyan, Mayako Michino, R Benjamin Free, David R Sibley, Jonathan A Javitch, J Robert Lane, Lei Shi
The dopamine D2 and D3 receptors (D2R and D3R) are important targets for antipsychotics and for the treatment of drug abuse. SB269652, a bitopic ligand that simultaneously binds both the orthosteric binding site (OBS) and a secondary binding pocket (SBP) in both D2R and D3R, was found to be a negative allosteric modulator. Previous studies identified Glu2.65 in the SBP to be a key determinant of both the affinity of SB269652 and the magnitude of its cooperativity with orthosteric ligands, as the E2.65A mutation decreased both of these parameters...
January 16, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29334795/progress-in-the-development-of-histamine-h3-receptor-antagonists-inverse-agonists-a-patent-review-2013-2017
#8
Dorota Łażewska, Katarzyna Kieć-Kononowicz
Since years, ligands blocking histamine H3 receptor (H3R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H3R antagonists/inverse agonists. Some of them have reached to clinical trials. Areas covered: Patent applications from January 2013 to September 2017 and the most important topics connected with H3R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials...
January 15, 2018: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/29334326/predicting-the-dopamine-d2-receptor-occupancy-of-ropinirole-in-rats-using-positron-emission-tomography-and-pharmacokinetic-pharmacodynamic-modeling
#9
Chenrong Huang, Ziteng Wang, Linsheng Liu, Xiaoxue Liu, Ji Dong, Qingqing Xu, Bin Zhang, Liyan Miao
The purpose of this study was to measure dopamine D2/3 receptor occupancy (RO) as a marker of the clinical efficacy of ropinirole in rats via positron emission tomography (PET) using 18F-fallypride as the radiotracer and to explore the relationship between dopamine RO and the plasma concentration of ropinirole via pharmacokinetic-pharmacodynamic modeling. Plasma was collected from 16 rats treated with one of four doses of ropinirole. For the time-dependent study, the data of 16 rats in the 15 mg/kg dose group at four time points were averaged, and another 24 rats were divided into three dose groups (5 mg/kg, 30 mg/kg and 60 mg/kg) for the dose-dependent study; the animals were assessed via 18F-fallypride PET scans...
January 15, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29332256/dopamine-dependent-social-information-processing-in-non-human-primates
#10
Young-A Lee, Sarah Lionnet, Akemi Kato, Yukiori Goto
RATIONALE: Dopamine (DA) is a neurotransmitter whose roles have been suggested in various aspects of brain functions. Recent studies in rodents have reported its roles in social function. However, how DA is involved in social information processing in primates has largely remained unclear. OBJECTIVES: We investigated prefrontal cortical (PFC) activities associated with social vs. nonsocial visual stimulus processing. METHODS: Near-infrared spectroscopy (NIRS) was applied to Japanese macaques, along with pharmacological manipulations of DA transmission, while they were gazing at social and nonsocial visual stimuli...
January 14, 2018: Psychopharmacology
https://www.readbyqxmd.com/read/29329984/infralimbic-dopamine-d2-receptors-mediate-glucocorticoid-induced-facilitation-of-auditory-fear-memory-extinction-in-rats
#11
Masoumeh Dadkhah, Payman Raise Abdullahi, Ali Rashidy-Pour, Hamid Reza Sameni, Abbas Ali Vafaei
The infralimbic (IL) cortex of the medial prefrontal cortex plays an important role in the extinction of fear memory. Also, it has been showed that both brain glucocorticoid and dopamine receptors are involved in many processes such as fear extinction that drive learning and memory; however, the interaction of these receptors in the IL cortex remains unclear. We examined a putative interaction between the effects of glucocorticoid and dopamine receptors stimulation in the IL cortex on fear memory extinction in an auditory fear conditioning paradigm in male rats...
January 9, 2018: Brain Research
https://www.readbyqxmd.com/read/29325847/amphetamine-induced-striatal-dopamine-release-measured-with-an-agonist-radiotracer-in%C3%A2-schizophrenia
#12
W Gordon Frankle, Jennifer Paris, Michael Himes, N Scott Mason, Chester A Mathis, Rajesh Narendran
BACKGROUND: Receptor imaging studies have reported increased amphetamine-induced dopamine release in subjects with schizophrenia (SCH) relative to healthy control subjects (HCs). A limitation of these studies, performed with D2/3 antagonist radiotracers, is the failure to provide information about D2/3 receptors configured in a state of high affinity for the agonists (i.e., D2/3 receptors coupled to G proteins [D2/3 HIGH]). The endogenous agonist dopamine binds with preference to D2/3 HIGH receptors relative to D2/3 LOW receptors, making it critical to understand the status of D2/3 HIGH receptors in SCH...
December 7, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/29325769/the-structural-determinants-of-the-bitopic-binding-mode-of-a-negative-allosteric-modulator-of-the-dopamine-d2-receptor
#13
Christopher J Draper-Joyce, Mayako Michino, Ravi Kumar Verma, Carmen Klein Herenbrink, Jeremy Shonberg, Anitha Kopinathan, Peter J Scammells, Ben Capuano, David M Thal, Jonathan A Javitch, Arthur Christopoulos, Lei Shi, J Robert Lane
SB269652 is a negative allosteric modulator of the dopamine D2 receptor (D2R) yet possesses structural similarity to ligands with a competitive mode of interaction. In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity...
January 8, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29324468/switching-antipsychotic-treatment-to-aripiprazole-in-psychotic-patients-with-neuroleptic-induced-tardive-dyskinesia-a-24-week-follow-up-study
#14
Chia-Hsiang Chan, Hung-Yu Chan, Yen-Ching Chen
Aripiprazole is a second-generation antipsychotics, acting as a partial dopamine D2 receptor agonist. Previous studies on aripiprazole for tardive dyskinesia (TD) treatment were limited and inconclusive. This study was aimed to examine the effectiveness of aripiprazole in psychotic patients with a pre-existing TD. This was an open-label 24-week prospective cohort study conducted in a public mental hospital in Northern Taiwan from January 2009 to February 2010.Psychotic patients were cross-titrated of prior antipsychotics with aripiprazole, and the severity of TD was assessed at baseline and at weeks 2, 4, 8, 12, 16, 20, and 24...
January 10, 2018: International Clinical Psychopharmacology
https://www.readbyqxmd.com/read/29324345/synthesis-and-biological-evaluation-of-a-series-of-multi-target-n-substituted-cyclic-imide-derivatives-with-potential-antipsychotic-effect
#15
Mingshuo Xu, Yu Wang, Feipu Yang, Chunhui Wu, Zhen Wang, Bin Ye, Xiangrui Jiang, Qingjie Zhao, Jianfeng Li, Yongjian Liu, Junchi Zhang, Guanghui Tian, Yang He, Jingshan Shen, Hualiang Jiang
In the present study, a series of multi-target N-substituted cyclic imide derivatives which possessed potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties were synthesized and evaluated as potential antipsychotics. Among these compounds, (3aR,4R,7S,7aS)-2-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride (3d) held a promising pharmacological profile. 3d not only showed potent and balanced in vitro activities on D2/5-HT1A/5-HT2A receptors, but also endowed with low to moderate activities on 5-HT2C, H1, α1A, M3 receptors and hERG channel, suggesting a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation...
January 4, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29318783/tak-063-a-novel-pde10a-inhibitor-with-balanced-activation-of-direct-and-indirect-pathways-provides-a-unique-opportunity-for-the-treatment-of-schizophrenia
#16
REVIEW
Kazunori Suzuki, Haruhide Kimura
The basal ganglia regulates motor, cognitive, and emotional behaviors. Dysfunction of dopamine system in this area is implicated in the pathophysiology of schizophrenia characterized by positive symptoms, negative symptoms, and cognitive deficits. Medium spiny neurons (MSNs) are principal output neurons of striatum in the basal ganglia. Similar to current antipsychotics with dopamine D2 receptor antagonism or partial agonism, phosphodiesterase 10A (PDE10A) inhibitors activate indirect pathway MSNs, leading to the expectation of therapeutic potential for the treatment of psychosis...
January 9, 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29304113/discovery-of-indolylpiperazinylpyrimidines-with-dual-target-profiles-at-adenosine-a2a-and-dopamine-d2-receptors-for-parkinson-s-disease-treatment
#17
Yi-Ming Shao, Xiaohua Ma, Priyankar Paira, Aaron Tan, Deron Raymond Herr, Kah Leong Lim, Chee Hoe Ng, Gopalakrishnan Venkatesan, Karl-Norbert Klotz, Stephanie Federico, Giampiero Spalluto, Siew Lee Cheong, Yu Zong Chen, Giorgia Pastorin
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects...
2018: PloS One
https://www.readbyqxmd.com/read/29304112/a-complex-network-approach-reveals-a-pivotal-substructure-of-genes-linked-to-schizophrenia
#18
Alfonso Monaco, Anna Monda, Nicola Amoroso, Alessandro Bertolino, Giuseppe Blasi, Pasquale Di Carlo, Marco Papalino, Giulio Pergola, Sabina Tangaro, Roberto Bellotti
Research on brain disorders with a strong genetic component and complex heritability, such as schizophrenia, has led to the development of brain transcriptomics. This field seeks to gain a deeper understanding of gene expression, a key factor in exploring further research issues. Our study focused on how genes are associated amongst each other. In this perspective, we have developed a novel data-driven strategy for characterizing genetic modules, i.e., clusters of strongly interacting genes. The aim was to uncover a pivotal community of genes linked to a target gene for schizophrenia...
2018: PloS One
https://www.readbyqxmd.com/read/29299155/neuroprotection-by-aripiprazole-against-%C3%AE-amyloid-induced-toxicity-by-p-ck2%C3%AE-activation-via-inhibition-of-gsk-3%C3%AE
#19
So Youn Park, Hwa Kyoung Shin, Won Suk Lee, Sun Sik Bae, Koanhoi Kim, Ki Whan Hong, Chi Dae Kim
Psychosis is reported over 30% of patients with Alzheimer's disease (AD) in clinics. Aripiprazole is an atypical antipsychotic drug with partial agonist activity at the D2 dopamine and 5-HT1A receptors with low side-effect profile. We identified aripiprazole is able to overcome the amyloid-β (Aβ)-evoked neurotoxicity and then increase the cell viability. This study elucidated the mechanism(s) by which aripiprazole ameliorates Aβ1-42-induced decreased neurite outgrowth and viability in neuronal cells. Pretreatment with aripiprazole increased Brain-derived neurotrophic factor (BDNF) mRNA and protein expressions in N2a cells...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29289668/involvement-of-the-dopaminergic-system-in-the-antidepressant-like-effect-of-the-lectin-isolated-from-the-red-marine-alga-solieria-filiformis-in-mice
#20
Ticiana Monteiro Abreu, Valdécio Silvano Monteiro, Ana Beatriz Souza Martins, Felipe Barros Teles, Renata Line da Conceição Rivanor, Érika Freitas Mota, Danielle S Macedo, Silvânia Maria Mendes de Vasconcelos, José Eduardo Ribeiro Honório Júnior, Norma Maria Barros Benevides
This study aimed at evaluating the antidepressant-like action of the marine alga Solieria filiformis lectin (SfL) and to investigate the participation of the monoaminergic system in this action. For this, male Swiss mice (n=10) were pretreated with intravenous injections (i.v.) of SfL (1, 3 or 9mg/kg) and submitted to open field (OFT), tail suspension (TST), forced swimming (FST), elevated plus-maze (EPMT) and hole-board tests (HBT). As controls, mice received sterile saline (i.v.), imipramine (10 or 30mg/kg; intraperitoneally - i...
December 28, 2017: International Journal of Biological Macromolecules
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