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[PMID]:28732063
[Au] Autor:Özkan M; Johnson NW; Sehirli US; Woodhall GL; Stanford IM
[Ad] Endereço:Aston Brain Centre, Aston University, School of Life and Health Sciences, Birmingham, United Kingdom.
[Ti] Título:Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex.
[So] Source:PLoS One;12(7):e0181633, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The loss of dopamine (DA) in Parkinson's is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1) and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 µM) and kainic acid (KA, 150 nM) elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84) and 34.97 ± 0.39 Hz (gamma, n = 84). Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1.
[Mh] Termos MeSH primário: Dopamina/metabolismo
Córtex Motor/metabolismo
Receptores Adrenérgicos alfa 1/metabolismo
Receptores de Dopamina D1/metabolismo
Receptores de Dopamina D2/metabolismo
[Mh] Termos MeSH secundário: 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia
Agonistas de Receptores Adrenérgicos alfa 1/farmacologia
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia
Animais
Benzazepinas/farmacologia
Agonistas de Dopamina/farmacologia
Antagonistas dos Receptores de Dopamina D2/farmacologia
Masculino
Córtex Motor/efeitos dos fármacos
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Transtornos Parkinsonianos/tratamento farmacológico
Transtornos Parkinsonianos/metabolismo
Prazosina/farmacologia
Quimpirol/farmacologia
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenergic alpha-1 Receptor Agonists); 0 (Adrenergic alpha-1 Receptor Antagonists); 0 (Benzazepines); 0 (Dopamine Agonists); 0 (Dopamine D2 Receptor Antagonists); 0 (Receptors, Adrenergic, alpha-1); 0 (Receptors, Dopamine D1); 0 (Receptors, Dopamine D2); 0 (SCH 23390); 20OP60125T (Quinpirole); 67287-49-4 (2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine); VTD58H1Z2X (Dopamine); XM03YJ541D (Prazosin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181633


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[PMID]:28666858
[Au] Autor:Schwalbe T; Kaindl J; Hübner H; Gmeiner P
[Ad] Endereço:Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander University Erlangen-Nürnberg, Schuhstraße 19, D-91052 Erlangen, Germany.
[Ti] Título:Potent haloperidol derivatives covalently binding to the dopamine D2 receptor.
[So] Source:Bioorg Med Chem;25(19):5084-5094, 2017 Oct 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The dopamine D receptor (D R) is a common drug target for the treatment of a variety of neurological disorders including schizophrenia. Structure based design of subtype selective D R antagonists requires high resolution crystal structures of the receptor and pharmacological tools promoting a better understanding of the protein-ligand interactions. Recently, we reported the development of a chemically activated dopamine derivative (FAUC150) designed to covalently bind the L94C mutant of the dopamine D receptor. Using FAUC150 as a template, we elaborated the design and synthesis of irreversible analogs of the potent antipsychotic drug haloperidol forming covalent D R-ligand complexes. The disulfide- and Michael acceptor-functionalized compounds showed significant receptor affinity and an irreversible binding profile in radioligand depletion experiments.
[Mh] Termos MeSH primário: Antagonistas dos Receptores de Dopamina D2/química
Antagonistas dos Receptores de Dopamina D2/farmacologia
Haloperidol/análogos & derivados
Haloperidol/farmacologia
Receptores de Dopamina D2/metabolismo
[Mh] Termos MeSH secundário: Antipsicóticos/química
Antipsicóticos/farmacologia
Seres Humanos
Ligantes
Simulação de Acoplamento Molecular
Mutação Puntual
Ligação Proteica
Ensaio Radioligante
Receptores de Dopamina D2/química
Receptores de Dopamina D2/genética
Esquizofrenia/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (DRD2 protein, human); 0 (Dopamine D2 Receptor Antagonists); 0 (Ligands); 0 (Receptors, Dopamine D2); J6292F8L3D (Haloperidol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE


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[PMID]:28603124
[Au] Autor:Khan A; Khan J; Irfan M; Naqvi SBS; Khan GM; Shoaib MH; Yousaf RI; Khan A
[Ad] Endereço:Department of Pharmacy, Quid-i-Azam University, Islamabad, Pakistan.
[Ti] Título:Validation and application of high performance liquid chromatographic method for the estimation of metoclopramide hydrochloride in plasma.
[So] Source:Pak J Pharm Sci;30(1):143-147, 2017 Jan.
[Is] ISSN:1011-601X
[Cp] País de publicação:Pakistan
[La] Idioma:eng
[Ab] Resumo:The objective of this study was validation of a reverse phase HPLC method for the estimation of metoclopramide HCl in plasma already validated for determination of metoclopramide HCl in tablets dosage form. A reverse chromatographic method was used for estimation of metoclopramide HCl with the mobile phase of acetonitrile, 20mM potassium dihydrogen phosphate buffer solution (pH 3.0 adjusted with orthophosphoric acid) in the ratio of 40: 60. The column used was Waters C18 3.9×300mm µBondapak (RP). The flow rate of the mobile phase was 2ml/ minute. The detector was set at the wavelength of 275nm. This method validated in plasma and was found to be linear, with correlation coefficient (R ), value of 0.9988, in the range of 48 ng/ml-0.25ng/ml. The method modified was accurate, precise, sensitive and showed good stability results. The % RSD of the retention time and peak area of metoclopramide HCl was 0.19% and 1.44% respectively. All the parameters such as specificity, linearity, range, accuracy, precision, system suitability, solution stability, detection and quantification limits were evaluated to validate this method and were found within the acceptance limits. The method can be effectively used for estimation of metoclopramide HCl in plasma.
[Mh] Termos MeSH primário: Cromatografia Líquida de Alta Pressão
Cromatografia de Fase Reversa
Antagonistas dos Receptores de Dopamina D2/sangue
Metoclopramida/sangue
[Mh] Termos MeSH secundário: Calibragem
Cromatografia Líquida de Alta Pressão/normas
Cromatografia de Fase Reversa/normas
Antagonistas dos Receptores de Dopamina D2/farmacocinética
Estabilidade de Medicamentos
Seres Humanos
Limite de Detecção
Modelos Lineares
Metoclopramida/farmacocinética
Padrões de Referência
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Dopamine D2 Receptor Antagonists); L4YEB44I46 (Metoclopramide)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE


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[PMID]:28577245
[Au] Autor:Bielefeldt K
[Ad] Endereço:George E. Wahlen VA Medical Center, Salt Lake City Specialty Care Center of Innovation and University of Utah, 500 Foothill Dr., Salt Lake City, UT, 84148, USA. Klaus.Bielefeldt@va.gov.
[Ti] Título:From Harmful Treatment to Secondary Gain: Adverse Event Reporting in Dyspepsia and Gastroparesis.
[So] Source:Dig Dis Sci;62(11):2999-3013, 2017 Nov.
[Is] ISSN:1573-2568
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Medical management of gastroparesis and functional dyspepsia remains difficult with several recent trials showing limited or no benefit. If treatment comes with only marginal improvements, concerns about adverse events become more relevant. We therefore examined the type and outcomes of side effects submitted to a public repository. METHODS: We searched the Federal Adverse Event Reporting System for reports associated with the treatment of dyspepsia or gastroparesis. Demographic data, medications used and implicated, side effects, and outcomes were abstracted for the years 2004-2015. RESULTS: Acid-suppressive agents and prokinetics were the most commonly listed medications with a stronger emphasis on prokinetics in gastroparesis. Submissions related to metoclopramide by far exceeded reports about other agents and mostly described tardive dyskinesia or other neurological concerns. They peaked around 2012, driven by submissions through legal workers. Most reports about metoclopramide described short-term use to prevent or treat nausea and vomiting. Concerns about acid-suppressive medications increased over time and spanned a wide spectrum of potential problems, including osteoporosis, worsening renal function, or cardiac events. CONCLUSION: Despite biasing factors, such as pending legal action, the voluntary repository of adverse events provides insight into current medical practice and its associated risk. Knowing about common and uncommon, but potentially serious risks may enable patients and providers to decide on effective and safe management strategies.
[Mh] Termos MeSH primário: Sistemas de Notificação de Reações Adversas a Medicamentos
Transtornos de Deglutição/tratamento farmacológico
Fármacos Gastrointestinais/efeitos adversos
Gastroparesia/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Antieméticos/efeitos adversos
Bases de Dados Factuais
Transtornos de Deglutição/diagnóstico
Transtornos de Deglutição/fisiopatologia
Antagonistas dos Receptores de Dopamina D2/efeitos adversos
Feminino
Gastroparesia/diagnóstico
Gastroparesia/fisiopatologia
Seres Humanos
Masculino
Metoclopramida/efeitos adversos
Meia-Idade
Segurança do Paciente
Inibidores da Bomba de Prótons/efeitos adversos
Medição de Risco
Fatores de Risco
Discinesia Tardia/induzido quimicamente
Fatores de Tempo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiemetics); 0 (Dopamine D2 Receptor Antagonists); 0 (Gastrointestinal Agents); 0 (Proton Pump Inhibitors); L4YEB44I46 (Metoclopramide)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170604
[St] Status:MEDLINE
[do] DOI:10.1007/s10620-017-4633-8


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[PMID]:28544038
[Au] Autor:da Costa IM; Cavalcanti JRLP; de Queiroz DB; de Azevedo EP; do Rêgo ACM; Araújo Filho I; Parente P; Botelho MA; Guzen FP
[Ad] Endereço:Laboratory of Experimental Neurology, Department of Biomedical Sciences, Health Science Center, State University of Rio Grande do Norte, Mossoró, RN, Brazil.
[Ti] Título:Supplementation with Herbal Extracts to Promote Behavioral and Neuroprotective Effects in Experimental Models of Parkinson's Disease: A Systematic Review.
[So] Source:Phytother Res;31(7):959-970, 2017 Jul.
[Is] ISSN:1099-1573
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Parkinson's disease (PD) consists of a neurodegenerative pathology that has received a considerable amount of attention because of its clinical manifestations. The most common treatment consists of administering the drugs levodopa and biperiden, which reduce the effectiveness of the disease and the progress of its symptoms. However, phytotherapy treatment of PD has shown great potential in retarding the loss of dopaminergic neurons and minimizing the behavioral abnormalities. The aim of this study is to systematically review the use of supplemental herbal plants with cellular protective effect and behavioral activity in in vivo and in vitro experimental models. A total of 20 studies were summarized, where the effectiveness of herbal extracts and their isolated bioactive compounds was observed in animal models for PD. The main neurochemical mechanisms found in these studies are schematically represented. The herbal extracts and their biocompounds have antioxidant, anti-apoptotic, and antiinflammatory properties, which contribute to avoiding neuronal loss. Reports show that besides acting on the biosynthesis of dopamine and its metabolites, these compounds prevent D2 receptors' hypersensitivity. It is suggested that further studies need be conducted to better understand the mechanisms of action of the bioactive compounds distributed in these plants. Copyright © 2017 John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Fármacos Neuroprotetores/farmacologia
Doença de Parkinson/tratamento farmacológico
Fitoterapia
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: Animais
Anti-Inflamatórios/farmacologia
Antioxidantes/farmacologia
Apoptose/efeitos dos fármacos
Modelos Animais de Doenças
Dopamina/biossíntese
Antagonistas dos Receptores de Dopamina D2/farmacologia
Neurônios Dopaminérgicos/efeitos dos fármacos
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Antioxidants); 0 (Dopamine D2 Receptor Antagonists); 0 (Neuroprotective Agents); 0 (Plant Extracts); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1002/ptr.5813


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[PMID]:28522405
[Au] Autor:Forray C; Buller R
[Ad] Endereço:Lundbeck Pharmaceuticals LLC, 215 College Road, Paramus, NJ 07652, USA. Electronic address: cafo@lundbeck.com.
[Ti] Título:Challenges and opportunities for the development of new antipsychotic drugs.
[So] Source:Biochem Pharmacol;143:10-24, 2017 Nov 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In spite of the significant impact that the serendipitous discovery of drugs with antipsychotic properties had on the care of patients with psychotic disorders, there are significant challenges when aiming at therapeutic goals such as remission, recovery, improved health-related quality of life and functioning. The efficacy and effectiveness of existing antipsychotic drugs fail to address the full spectrum of symptoms and functional deficits that currently prevent patients with psychotic disorders from achieving fulfilling lives. The study of the pharmacological mechanism of action has increased our knowledge on molecular targets and brain circuits related to the antipsychotic properties of this drug class. However, our understanding of how these molecular targets and brain circuits relate to other aspects of disease pathophysiology like cognitive impairment and negative symptoms is incomplete although these are significant clinical unmet needs. Currently, there is still an important knowledge gap between psychopathology and pathophysiology in schizophrenia research. This may have contributed to some recent costly failures of large clinical development programs for drugs targeted at glutamatergic function and nicotinic receptors. The lack of success of these pharmacological approaches to achieve clinical validation raises important questions concerning the underlying hypothesis that guided the choice of molecular targets, and about the predictive validity of translational models that supported the rationale for testing these drugs in clinical studies. From a clinical perspective there is a need to more strongly consider the disease heterogeneity linked to the use of the current diagnostic classification of subjects and to the validity of the psychopathological constructs and assessments that are used to assess clinical outcomes. A paradigm shift in the development of drugs for schizophrenia is needed. This will require among other addressing: the shortcomings of a single diagnostic entity; the needs for in depth clinical phenotyping to leverage the findings of schizophrenia genetics and advance the understanding of the disease biology; the symptom domains that are the major sources of disability in order to improve functional outcomes beyond current treatment options. In spite of the progress achieved during the last century the task ahead is still daunting and will require the efforts of scientists and clinicians through inclusive public-private partnerships and consortia to create the scientific basis for new therapeutic approaches to schizophrenia.
[Mh] Termos MeSH primário: Antipiréticos
Antagonistas dos Receptores de Dopamina D2
Descoberta de Drogas/métodos
Esquizofrenia/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Antipiréticos/efeitos adversos
Antipiréticos/farmacologia
Antipiréticos/uso terapêutico
Disfunção Cognitiva/induzido quimicamente
Transtorno Depressivo/induzido quimicamente
Antagonistas dos Receptores de Dopamina D2/efeitos adversos
Antagonistas dos Receptores de Dopamina D2/farmacologia
Antagonistas dos Receptores de Dopamina D2/uso terapêutico
Indústria Farmacêutica
Seres Humanos
Transtornos Mentais
Esquizofrenia/genética
Esquizofrenia/metabolismo
Esquizofrenia/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antipyretics); 0 (Dopamine D2 Receptor Antagonists)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE


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[PMID]:28473458
[Au] Autor:Thomsen M; Barrett AC; Butler P; Negus SS; Caine SB
[Ad] Endereço:Alcohol and Drug Abuse Research Center, McLean Hospital, Belmont, Massachusetts (M.T., A.C.B., S.B.C.); Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts (M.T., A.C.B., S.B.C.); Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, University of Copenhagen, Copenhagen,
[Ti] Título:Effects of Acute and Chronic Treatments with Dopamine D and D Receptor Ligands on Cocaine versus Food Choice in Rats.
[So] Source:J Pharmacol Exp Ther;362(1):161-176, 2017 Jul.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dopamine D receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, nondrug reinforcer. This study compared acute and chronic effects of dopamine D - and D -preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D agonist -(-)-norpropylapomorphine (NPA) and antagonist L-741,626 [3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1 -indole] produced leftward and rightward shifts in cocaine dose-effect curves, respectively, whereas the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, the effects of -(-)-norpropylapomorphine and L-741,626 on cocaine self-administration showed marked tolerance, whereas suppression of food-reinforced behavior persisted. Acute effects of the D ligands were less systematic and most consistent with nonselective decreases in cocaine- and food-maintained responding. Chronically, the D agonist PF-592,379 [5-[(2 ,5 )-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine] increased cocaine choice, whereas an intermediate dose of the D antagonist PG01037 [ -[( )-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide] produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance to this effect developed, and lower and higher doses were ineffective. D ligands failed to significantly modify total cocaine intake but caused persistent decreases in food intake. Thus, D -and D -preferring ligands showed distinct profiles, consistent with different pharmacological actions. In addition, these results highlight the role of acute versus chronic treatment as a determinant of test drug effects. With the possible exception of the D antagonist PG01037, no ligand was promising in terms of cocaine addiction treatment.
[Mh] Termos MeSH primário: Comportamento de Escolha/efeitos dos fármacos
Cocaína/farmacologia
Alimentos
Receptores de Dopamina D2/efeitos dos fármacos
Receptores de Dopamina D3/efeitos dos fármacos
[Mh] Termos MeSH secundário: Aminopiridinas/farmacologia
Animais
Benzamidas/farmacologia
Condicionamento Operante/efeitos dos fármacos
Agonistas de Dopamina/farmacologia
Antagonistas de Dopamina/farmacologia
Antagonistas dos Receptores de Dopamina D2/farmacologia
Relação Dose-Resposta a Droga
Tolerância a Medicamentos
Indóis/farmacologia
Ligantes
Masculino
Morfolinas/farmacologia
Piperidinas/farmacologia
Piridinas/farmacologia
Ratos Sprague-Dawley
Reforço (Psicologia)
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminopyridines); 0 (Benzamides); 0 (DRD2 protein, rat); 0 (Dopamine Agonists); 0 (Dopamine Antagonists); 0 (Dopamine D2 Receptor Antagonists); 0 (Drd3 protein, rat); 0 (Indoles); 0 (Ligands); 0 (Morpholines); 0 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide); 0 (PF 592379); 0 (Piperidines); 0 (Pyridines); 0 (Receptors, Dopamine D2); 0 (Receptors, Dopamine D3); 81226-60-0 (3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole); I5Y540LHVR (Cocaine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170506
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.241141


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[PMID]:28443355
[Au] Autor:Wang SM; Han C; Lee SJ; Jun TY; Patkar AA; Masand PS; Pae CU
[Ad] Endereço:a Department of Psychiatry , The Catholic University of Korea College of Medicine , Seoul , Republic of Korea.
[Ti] Título:Investigational dopamine antagonists for the treatment of schizophrenia.
[So] Source:Expert Opin Investig Drugs;26(6):687-698, 2017 Jun.
[Is] ISSN:1744-7658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Schizophrenia is a debilitating illness with a chronic impact on social function and daily living. Although various antipsychotics are available, there are still many challenges and unmet needs. Thus, many compounds with diverse mechanisms have been investigated, but all approved antipsychotics still require interactions with dopamine D receptors. Areas covered: We searched for investigational drugs using the key words 'dopamine' and 'schizophrenia' in American and European clinical trial registers (clinicaltrials.gov; clinicaltrialsregister.eu). Published articles were searched in PubMed, Embase, Medline, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Web of Science and the Cochrane Central Register of Controlled Trials Library. Expert opinion: The prospect of developing a dopamine antagonist is hopeful. Brexpiprazole and cariprazine, which were agents listed as 'investigational dopamine antagonists,' just received FDA approval. Novel agents such as BL 1020, ITI-007, and JNJ-37822681 have solid published data available, and agents such as L-THP, Lu AF35700, S33138, and SB-773812 are under vigorous investigation. However, the expected benefits of the newly developed antagonists may not be great because they offer little enhanced efficacy for negative symptoms, cognition and functional outcomes.
[Mh] Termos MeSH primário: Antipsicóticos/uso terapêutico
Antagonistas de Dopamina/uso terapêutico
Esquizofrenia/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Antipsicóticos/farmacologia
Antagonistas de Dopamina/farmacologia
Antagonistas dos Receptores de Dopamina D2/farmacologia
Antagonistas dos Receptores de Dopamina D2/uso terapêutico
Desenho de Drogas
Drogas em Investigação/farmacologia
Drogas em Investigação/uso terapêutico
Seres Humanos
Receptores de Dopamina D2/efeitos dos fármacos
Receptores de Dopamina D2/metabolismo
Esquizofrenia/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (Dopamine Antagonists); 0 (Dopamine D2 Receptor Antagonists); 0 (Drugs, Investigational); 0 (Receptors, Dopamine D2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE
[do] DOI:10.1080/13543784.2017.1323870


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[PMID]:28265019
[Au] Autor:Rossi M; Fasciani I; Marampon F; Maggio R; Scarselli M
[Ad] Endereço:Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (M.R.); Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy (I.F., F.M., R.M.); Department of Transl
[Ti] Título:The First Negative Allosteric Modulator for Dopamine D and D Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs.
[So] Source:Mol Pharmacol;91(6):586-594, 2017 Jun.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:D and D dopamine receptors belong to the largest family of cell surface proteins in eukaryotes, the G protein-coupled receptors (GPCRs). Considering their crucial physiologic functions and their relatively accessible cellular locations, GPCRs represent one of the most important classes of therapeutic targets. Until recently, the only strategy to develop drugs regulating GPCR activity was through the identification of compounds that directly acted on the orthosteric sites for endogenous ligands. However, many efforts have recently been made to identify small molecules that are able to interact with allosteric sites. These sites are less well-conserved, therefore allosteric ligands have greater selectivity on the specific receptor. Strikingly, the use of allosteric modulators can provide specific advantages, such as an increased selectivity for GPCR subunits and the ability to introduce specific beneficial therapeutic effects without disrupting the integrity of complex physiologically regulated networks. In 2010, our group unexpectedly found that -[(1r,4r)-4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide (SB269652), a compound supposed to interact with the orthosteric binding site of dopamine receptors, was actually a negative allosteric modulator of D - and D -receptor dimers, thus identifying the first allosteric small molecule acting on these important therapeutic targets. This review addresses the progress in understanding the molecular mechanisms of interaction between the negative modulator SB269652 and D and D dopamine receptor monomers and dimers, and surveys the prospects for developing new dopamine receptor allosteric drugs with SB269652 as the leading compound.
[Mh] Termos MeSH primário: Antipsicóticos/farmacologia
Antagonistas dos Receptores de Dopamina D2/farmacologia
Indóis/farmacologia
Isoquinolinas/farmacologia
Receptores de Dopamina D2/fisiologia
Receptores de Dopamina D3/antagonistas & inibidores
Receptores de Dopamina D3/fisiologia
[Mh] Termos MeSH secundário: Regulação Alostérica/efeitos dos fármacos
Regulação Alostérica/fisiologia
Sítio Alostérico/efeitos dos fármacos
Sítio Alostérico/fisiologia
Animais
Antipsicóticos/metabolismo
Sítios de Ligação/efeitos dos fármacos
Sítios de Ligação/fisiologia
Antagonistas dos Receptores de Dopamina D2/metabolismo
Seres Humanos
Indóis/metabolismo
Isoquinolinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (1H-indole-2-carboxylic acid (4-(2-(cyano-3,4-dihydro-1H-isoquinolin-2-yl)ethyl)cyclohexyl)amide); 0 (Antipsychotic Agents); 0 (Dopamine D2 Receptor Antagonists); 0 (Indoles); 0 (Isoquinolines); 0 (Receptors, Dopamine D2); 0 (Receptors, Dopamine D3)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170614
[Lr] Data última revisão:
170614
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170308
[St] Status:MEDLINE
[do] DOI:10.1124/mol.116.107607


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[PMID]:28264982
[Au] Autor:Evans RC; Zhu M; Khaliq ZM
[Ad] Endereço:Cellular Neurophysiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
[Ti] Título:Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels.
[So] Source:J Neurosci;37(13):3704-3720, 2017 Mar 29.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:While there is growing appreciation for diversity among ventral tegmental area dopamine neurons, much less is known regarding functional heterogeneity among the substantia nigra pars compacta (SNc) neurons. Here, we show that calbindin-positive dorsal tier and calbindin-negative ventral tier SNc dopaminergic neurons in mice comprise functionally distinct subpopulations distinguished by their dendritic calcium signaling, rebound excitation, and physiological responses to dopamine D2-receptor (D2) autoinhibition. While dopamine is known to inhibit action potential backpropagation, our experiments revealed an unexpected enhancement of excitatory responses and dendritic calcium signals in the presence of D2-receptor inhibition. Specifically, dopamine inhibition and direct hyperpolarization enabled the generation of low-threshold depolarizations that occurred in an all-or-none or graded manner, due to recruitment of T-type calcium channels. Interestingly, these effects occurred selectively in calbindin-negative dopaminergic neurons within the SNc. Thus, calbindin-positive and calbindin-negative SNc neurons differ substantially in their calcium channel composition and efficacy of excitatory inputs in the presence of dopamine inhibition. Substantia nigra dopaminergic neurons can be divided into two populations: the calbindin-negative ventral tier, which is vulnerable to neurodegeneration in Parkinson's disease, and the calbindin-positive dorsal tier, which is relatively resilient. Although tonic firing is similar in these subpopulations, we find that their responses to dopamine-mediated inhibition are strikingly different. During inhibition, calbindin-negative neurons exhibit increased sensitivity to excitatory inputs, which can then trigger large dendritic calcium transients due to strong expression of T-type calcium channels. Therefore, SNc neurons differ substantially in their calcium channel composition, which may contribute to their differential vulnerability. Furthermore, T-currents increase excitation efficacy onto calbindin-negative cells during dopamine inhibition, suggesting that shared inputs are differentially processed in subpopulations resulting in distinct downstream dopamine signals.
[Mh] Termos MeSH primário: Calbindinas/metabolismo
Canais de Cálcio Tipo T/metabolismo
Sinalização do Cálcio/fisiologia
Neurônios Dopaminérgicos/classificação
Neurônios Dopaminérgicos/fisiologia
Substância Negra/fisiologia
[Mh] Termos MeSH secundário: Animais
Sinalização do Cálcio/efeitos dos fármacos
Células Cultivadas
Dopamina/metabolismo
Antagonistas dos Receptores de Dopamina D2/administração & dosagem
Neurônios Dopaminérgicos/efeitos dos fármacos
Feminino
Ativação do Canal Iônico/efeitos dos fármacos
Ativação do Canal Iônico/fisiologia
Masculino
Camundongos
Camundongos Transgênicos
Inibição Neural/efeitos dos fármacos
Inibição Neural/fisiologia
Receptores de Dopamina D2/metabolismo
Substância Negra/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calbindins); 0 (Calcium Channels, T-Type); 0 (DRD2 protein, mouse); 0 (Dopamine D2 Receptor Antagonists); 0 (Receptors, Dopamine D2); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170308
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0117-17.2017



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