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Article ; Online: Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity.

Ku, Therese C / Cao, Jianjing / Won, Sung Joon / Guo, Jiqing / Camacho-Hernandez, Gisela A / Okorom, Amarachi V / Salomon, Kristine Walloe / Lee, Kuo Hao / Loland, Claus J / Duff, Henry J / Shi, Lei / Newman, Amy Hauck

ACS pharmacology & translational science

2024 Volume 7, Issue 2, Page(s) 515–532

Abstract: Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered "atypical" dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be ... ...

Abstract	Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered "atypical" dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be useful as medications to treat PSUD. Lead candidates (e.g., JJC8-091,
Language	English
Publishing date	2024-01-05
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.3c00322
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Global research trends in CRISPR-related technologies associated with extracellular vesicles from 2015 to 2022: a bibliometric, dynamic, and visualized study.

Lin, Jianjing / Jia, Shicheng / Jiao, Zilu / Chen, Jiayou / Li, Wei / Cao, Fuyang / Zhang, Xintao

Cellular & molecular biology letters

2023 Volume 28, Issue 1, Page(s) 99

Abstract: Purpose: This study aims to explore the emerging trends, dynamic development, and research hotspots of clustered regularly interspaced short palindromic repeats (CRISPR) technology associated with extracellular vesicles during the past 7 years and ... ...

Abstract	Purpose: This study aims to explore the emerging trends, dynamic development, and research hotspots of clustered regularly interspaced short palindromic repeats (CRISPR) technology associated with extracellular vesicles during the past 7 years and demonstrate them by visualization. Methods: A total of 219 records related to CRISPR technology associated with extracellular vesicles from 2015 to 2022 in the Web of Science Core Collection (WoSCC) database were collected. R language, VOSviewer, CiteSpace, and GraphpadPrism software packages were used to analyze the history of this research, the general characteristics of the literature, and keywords. Finally, the hotspots and latest trends in CRISPR technology associated with extracellular vesicles are predicted. Results: A total of 219 articles were collected for this study. The production of publications about CRISPR technology associated with extracellular vesicles has increased annually. Researchers from China, the USA, and Germany made the most important contributions to this trend, while RLUK Research Libraries UK offers the largest amount of literature in this field. Shenzhen University, Nanjing Medicine University, and Peking University exhibited the closest cooperation. Additionally, active topics burst during different periods, as identified according to 317 keywords belonging to 39 disciplines. Keywords were clustered into seven research subareas, namely exosome, nanovesicles, DNA, gene editing, gene therapy, cancer therapy, and endometrial stromal cells. The alluvial map of keywords reveals that the most enduring concepts are gene therapy, nanovesicles, etc., while the emerging keywords are genome, protein delivery, plasma, etc. CONCLUSIONS: We reviewed 219 previous publications and conducted the first bibliometric study of CRISPR technology related to extracellular vesicles from 2015 to 2022. This comprehensive summary constructed a knowledge map and demonstrates the trends in this area. The current trends and potential hotpots for this topic are also identified, which will be a great help for researchers in the future.
MeSH term(s)	Humans ; Clustered Regularly Interspaced Short Palindromic Repeats ; Extracellular Vesicles ; Exosomes ; Bibliometrics ; Databases, Factual
Language	English
Publishing date	2023-12-02
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	2108724-6
ISSN	1689-1392 ; 1689-1392
ISSN (online)	1689-1392
ISSN	1689-1392
DOI	10.1186/s11658-023-00507-z
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Article ; Online: Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats.

Hersey, Melinda / Mereu, Maddalena / Jones, Claire S / Bartole, Mattingly K / Chen, Andy Y / Cao, Jianjing / Hiranita, Takato / Chun, Lauren E / Lopez, Jessica P / Katz, Jonathan L / Newman, Amy Hauck / Tanda, Gianluigi

The European journal of neuroscience

2024

Abstract: Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce ... ...

Abstract	Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.
Language	English
Publishing date	2024-03-05
Publishing country	France
Document type	Journal Article
ZDB-ID	645180-9
ISSN	1460-9568 ; 0953-816X
ISSN (online)	1460-9568
ISSN	0953-816X
DOI	10.1111/ejn.16293
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Article ; Online: 3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder.

Doyle, Michelle R / Peng, Lindsey N / Cao, Jianjing / Rice, Kenner C / Newman, Amy Hauck / Collins, Gregory T

The Journal of pharmacology and experimental therapeutics

2023 Volume 384, Issue 3, Page(s) 353–362

Abstract: Despite decades of research, there are no medications approved by the United States Food and Drug Administration to treat stimulant use disorders. Self-administration procedures are widely used to screen candidate medications for stimulant use disorder, ... ...

Abstract	Despite decades of research, there are no medications approved by the United States Food and Drug Administration to treat stimulant use disorders. Self-administration procedures are widely used to screen candidate medications for stimulant use disorder, although preclinical reductions in stimulant self-administration have not translated to meaningful reductions in stimulant use in humans. One possible reason for this discordance is that most preclinical studies evaluate candidate medications under conditions that promote predictable, and well-regulated patterns of drug-taking rather than the dysregulated and/or compulsive patterns of drug-taking characteristic of a stimulant use disorder. A subset of rats ("high-responders") that self-administer 3,4-methelyendioxypyrovalerone (MDPV), a monoamine uptake inhibitor, develop high levels of dysregulated drug-taking consistent with behaviors related to stimulant use disorders. Because MDPV acts on dopamine, serotonin (5-HT), and sigma receptor systems, the current studies compared the potency and effectiveness of a dopamine D
MeSH term(s)	Animals ; Female ; Humans ; Male ; Rats ; Cocaine ; Dopamine ; Dose-Response Relationship, Drug ; Haloperidol ; Receptors, sigma ; Self Administration ; Serotonin ; Synthetic Cathinone
Chemical Substances	Cocaine (I5Y540LHVR) ; Dopamine (VTD58H1Z2X) ; Haloperidol (J6292F8L3D) ; Receptors, sigma ; Serotonin (333DO1RDJY) ; Synthetic Cathinone
Language	English
Publishing date	2023-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.122.001419
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Article ; Online: Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors.

Ecevitoglu, Alev / Meka, Nicolette / Rotolo, Renee A / Edelstein, Gayle A / Srinath, Sonya / Beard, Kathryn R / Carratala-Ros, Carla / Presby, Rose E / Cao, Jianjing / Okorom, Amarachi / Newman, Amy H / Correa, Mercè / Salamone, John D

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2024

Abstract: People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort- ...

Abstract	People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.
Language	English
Publishing date	2024-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-024-01826-1
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Article ; Online: The Effects of the Dopamine Transporter Ligands JJC8-088 and JJC8-091 on Cocaine versus Food Choice in Rhesus Monkeys.

Rahimi, Omeed / Cao, Jianjing / Lam, Jenny / Childers, Steven R / Rais, Rana / Porrino, Linda J / Newman, Amy Hauck / Nader, Michael A

The Journal of pharmacology and experimental therapeutics

2022 Volume 384, Issue 3, Page(s) 372–381

Abstract: Although there are no Food and Drug Administration-approved treatments for cocaine use disorder, several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine ... ...

Abstract	Although there are no Food and Drug Administration-approved treatments for cocaine use disorder, several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine versus food schedule of reinforcement. First, binding to striatal DAT was examined in cocaine-naïve monkey tissue. Next, intravenous pharmacokinetics of both JJC compounds were evaluated in cocaine-experienced male monkeys (
MeSH term(s)	Male ; Rats ; Animals ; Cocaine/pharmacology ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Macaca mulatta/metabolism ; Dopamine Uptake Inhibitors/pharmacology ; Self Administration ; Dose-Response Relationship, Drug
Chemical Substances	Cocaine (I5Y540LHVR) ; Dopamine Plasma Membrane Transport Proteins ; JJC8-091 ; JJC8-088 ; Dopamine Uptake Inhibitors
Language	English
Publishing date	2022-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.122.001363
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Article ; Online: Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release.

Keighron, Jacqueline D / Bonaventura, Jordi / Li, Yang / Yang, Jae-Won / DeMarco, Emily M / Hersey, Melinda / Cao, Jianjing / Sandtner, Walter / Michaelides, Michael / Sitte, Harald H / Newman, Amy Hauck / Tanda, Gianluigi

Translational psychiatry

2023 Volume 13, Issue 1, Page(s) 202

Abstract: Typical and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, resulting in markedly different effects on behavior, neurochemistry, and potential for addiction. ...

Abstract	Typical and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, resulting in markedly different effects on behavior, neurochemistry, and potential for addiction. Here we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DUIs, as measured via voltammetry procedures. While both classes of DUIs reduced DA clearance rate, an effect significantly related to their DAT affinity, only typical DUIs elicited a significant stimulation of evoked DA release, an effect unrelated to their DAT affinity, which suggests a mechanism of action other than or in addition to DAT blockade. When given in combination, typical DUIs enhance the stimulatory effects of cocaine on evoked DA release while atypical DUIs blunt them. Pretreatments with an inhibitor of CaMKIIα, a kinase that interacts with DAT and that regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted the effects of cocaine on evoked DA release. Our results suggest a role for CaMKIIα in modulating the effects of cocaine on evoked DA release without affecting cocaine inhibition of DA reuptake. This effect is related to a specific DAT conformation stabilized by cocaine. Moreover, atypical DUIs, which prefer a distinct DAT conformation, blunt cocaine's neurochemical and behavioral effects, indicating a unique mechanism underlying their potential as medications for treating psychostimulant use disorder.
MeSH term(s)	Cocaine/pharmacology ; Dopamine ; Dopamine Plasma Membrane Transport Proteins ; Dopamine Uptake Inhibitors/pharmacology ; Central Nervous System Stimulants ; Calcium-Calmodulin-Dependent Protein Kinases
Chemical Substances	Cocaine (I5Y540LHVR) ; Dopamine (VTD58H1Z2X) ; Dopamine Plasma Membrane Transport Proteins ; Dopamine Uptake Inhibitors ; Central Nervous System Stimulants ; Calcium-Calmodulin-Dependent Protein Kinases (EC 2.7.11.17)
Language	English
Publishing date	2023-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-023-02493-4
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Article ; Online: Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile.

Okorom, Amarachi V / Camacho-Hernandez, Gisela Andrea / Salomon, Kristine / Lee, Kuo Hao / Ku, Therese C / Cao, Jianjing / Won, Sung Joon / Friedman, Jacob / Lam, Jenny / Paule, James / Rais, Rana / Klein, Benjamin / Xi, Zheng-Xiong / Shi, Lei / Loland, Claus J / Newman, Amy Hauck

Journal of medicinal chemistry

2023 Volume 67, Issue 1, Page(s) 709–727

Abstract: Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol ( ...

Abstract	Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (
MeSH term(s)	Rats ; Mice ; Animals ; Dopamine Plasma Membrane Transport Proteins ; Amines/pharmacology ; Structure-Activity Relationship ; Serotonin Plasma Membrane Transport Proteins/metabolism ; Cocaine ; Central Nervous System Stimulants/pharmacology ; Piperidines/pharmacology
Chemical Substances	Dopamine Plasma Membrane Transport Proteins ; Amines ; Serotonin Plasma Membrane Transport Proteins ; Cocaine (I5Y540LHVR) ; Central Nervous System Stimulants ; Piperidines
Language	English
Publishing date	2023-12-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c02037
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Article ; Online: Progress in agonist therapy for substance use disorders: Lessons learned from methadone and buprenorphine.

Jordan, Chloe J / Cao, Jianjing / Newman, Amy Hauck / Xi, Zheng-Xiong

Neuropharmacology

2019 Volume 158, Page(s) 107609

Abstract: Substance use disorders (SUD) are serious public health problems worldwide. Although significant progress has been made in understanding the neurobiology of drug reward and the transition to addiction, effective pharmacotherapies for SUD remain limited ... ...

Abstract	Substance use disorders (SUD) are serious public health problems worldwide. Although significant progress has been made in understanding the neurobiology of drug reward and the transition to addiction, effective pharmacotherapies for SUD remain limited and a majority of drug users relapse even after a period of treatment. The United States Food and Drug Administration (FDA) has approved several medications for opioid, nicotine, and alcohol use disorders, whereas none are approved for the treatment of cocaine or other psychostimulant use disorders. The medications approved by the FDA for the treatment of SUD can be divided into two major classes - agonist replacement therapies, such as methadone and buprenorphine for opioid use disorders (OUD), nicotine replacement therapy (NRT) and varenicline for nicotine use disorders (NUD), and antagonist therapies, such as naloxone for opioid overdose and naltrexone for promoting abstinence. In the present review, we primarily focus on the pharmacological rationale of agonist replacement strategies in treatment of opioid dependence, and the potential translation of this rationale to new therapies for cocaine use disorders. We begin by describing the neural mechanisms underlying opioid reward, followed by preclinical and clinical findings supporting the utility of agonist therapies in the treatment of OUD. We then discuss recent progress of agonist therapies for cocaine use disorders based on lessons learned from methadone and buprenorphine. We contend that future studies should identify agonist pharmacotherapies that can facilitate abstinence in patients who are motivated to quit their illicit drug use. Focusing on those that are able to achieve abstinence from cocaine will provide a platform to broaden the effectiveness of medication and psychosocial treatment strategies for this underserved population. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.
MeSH term(s)	Analgesics, Opioid/therapeutic use ; Buprenorphine/therapeutic use ; Central Nervous System Stimulants/therapeutic use ; Cocaine-Related Disorders/drug therapy ; Dextroamphetamine/therapeutic use ; Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors ; Dopamine Uptake Inhibitors/therapeutic use ; Drug Development ; Humans ; Methadone/therapeutic use ; Methylphenidate/therapeutic use ; Modafinil/therapeutic use ; Nicotinic Agonists/therapeutic use ; Opiate Substitution Treatment ; Opioid-Related Disorders/drug therapy ; Opioid-Related Disorders/metabolism ; Oxalates ; Piperazines ; Receptors, Opioid, mu/agonists ; Tobacco Use Disorder/drug therapy ; Tropanes/therapeutic use ; Varenicline/therapeutic use
Chemical Substances	3beta-(4-chlorophenyl) tropane-2beta-(3-(4'-methylphenyl) isoxazol-5-yl) hydrochloride ; Analgesics, Opioid ; Central Nervous System Stimulants ; Dopamine Plasma Membrane Transport Proteins ; Dopamine Uptake Inhibitors ; JJC8-091 ; Nicotinic Agonists ; Oxalates ; Piperazines ; Receptors, Opioid, mu ; Tropanes ; Methylphenidate (207ZZ9QZ49) ; Buprenorphine (40D3SCR4GZ) ; Modafinil (R3UK8X3U3D) ; Dextroamphetamine (TZ47U051FI) ; Methadone (UC6VBE7V1Z) ; Varenicline (W6HS99O8ZO)
Language	English
Publishing date	2019-04-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2019.04.015
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Article ; Online: Structure Activity Relationships for a Series of Eticlopride-Based Dopamine D

Shaik, Anver Basha / Boateng, Comfort A / Battiti, Francisco O / Bonifazi, Alessandro / Cao, Jianjing / Chen, Li / Chitsazi, Rezvan / Ravi, Saiprasad / Lee, Kuo Hao / Shi, Lei / Newman, Amy Hauck

Journal of medicinal chemistry

2021 Volume 64, Issue 20, Page(s) 15313–15333

Abstract: The crystal structure of the dopamine ... ...

Abstract	The crystal structure of the dopamine D
MeSH term(s)	Dose-Response Relationship, Drug ; Humans ; Ligands ; Models, Molecular ; Molecular Structure ; Receptors, Dopamine D2/metabolism ; Receptors, Dopamine D3/metabolism ; Salicylamides/chemical synthesis ; Salicylamides/chemistry ; Salicylamides/pharmacology ; Structure-Activity Relationship
Chemical Substances	Ligands ; Receptors, Dopamine D2 ; Receptors, Dopamine D3 ; Salicylamides ; eticlopride (J8M468HBH4)
Language	English
Publishing date	2021-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c01353
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