更新于：2024-11-01

D1 receptor x α1B-AR x α1A-AR x D2 receptor

更新于：2024-11-01

基本信息

关联

项与 D1 receptor x α1B-AR x α1A-AR x D2 receptor 相关的药物

Thioproperazine

靶点

D1 receptor x D2 receptor x α1A-AR x α1B-AR

作用机制

D1 receptor拮抗剂 [+3]

在研机构-

原研机构-

在研适应症-

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区-

首次获批日期1800-01-20

Thioridazine

硫利达嗪

靶点

5-HT2A receptor x D1 receptor x D2 receptor x hERG x α1A-AR x α1B-AR

作用机制

5-HT2A receptor拮抗剂 [+5]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床3期

首次获批国家/地区

美国

首次获批日期1978-10-18

项与 D1 receptor x α1B-AR x α1A-AR x D2 receptor 相关的临床试验

CTR20221306 / Recruiting临床3期

TP21注射液用于TACE治疗肝细胞癌的有效性和安全性的随机、开放、平行对照、多中心Ⅲ期临床试验

主要目的：比较TP21与盐酸表柔比星用于TACE治疗不可切除肝细胞癌的有效性。次要目的：评价TP21用于TACE治疗不可切除肝细胞癌的安全性。

开始日期2022-08-29

申办/合作机构

北京索普兴大医药研究有限公司

CTR20181994 / Recruiting临床2期

TP21注射液用于TACE治疗肝细胞癌的有效性和安全性的随机、开放、平行对照、多中心探索性临床试验

初步探索TP21用于TACE治疗肝细胞癌的有效性。以盐酸表柔比星为对照，比较TP21或TP21联合盐酸表柔比星用于TACE治疗肝细胞癌的疗效差异。次要目的：评价TP21用于TACE治疗肝细胞癌的安全性。

开始日期2019-03-15

申办/合作机构

北京索普兴大医药研究有限公司

[+1]

100 项与 D1 receptor x α1B-AR x α1A-AR x D2 receptor 相关的临床结果

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100 项与 D1 receptor x α1B-AR x α1A-AR x D2 receptor 相关的转化医学

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0 项与 D1 receptor x α1B-AR x α1A-AR x D2 receptor 相关的专利（医药）

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项与 D1 receptor x α1B-AR x α1A-AR x D2 receptor 相关的文献（医药）

2019-01-01·Progress in Neuro-Psychopharmacology and Biological Psychiatry2区 · 医学

The effects of single-dose injections of modafinil and methamphetamine on epigenetic and functional markers in the mouse medial prefrontal cortex: potential role of dopamine receptors

2区 · 医学

Article

作者: Sosa, Máximo H ; Bisagno, Verónica ; García-Rill, Edgar ; Urbano, Francisco J ; González, Betina ; Bernardi, Alejandra ; Jayanthi, Subramaniam ; Cadet, Jean-Lud ; Gomez, Natalia ; Torres, Oscar V

METH use causes neuroadaptations that negatively impact the prefrontal cortex (PFC) leading to addiction and associated cognitive decline in animals and humans. In contrast, modafinil enhances cognition by increasing PFC function. Accumulated evidence indicates that psychostimulant drugs, including modafinil and METH, regulate gene expression via epigenetic modifications. In this study, we measured the effects of single-dose injections of modafinil and METH on the protein levels of acetylated histone H3 (H3ac) and H4ac, deacetylases HDAC1 and HDAC2, and of the NMDA subunit GluN1 in the medial PFC (mPFC) of mice euthanized 1 h after drug administration. To test if dopamine (DA) receptors (DRs) participate in the biochemical effects of the two drugs, we injected the D1Rs antagonist, SCH23390, or the D2Rs antagonist, raclopride, 30 min before administration of METH and modafinil. We evaluated each drug effect on glutamate synaptic transmission in D1R-expressing layer V pyramidal neurons. We also measured the enrichment of H3ac and H4ac at the promoters of several genes including DA, NE, orexin, histamine, and glutamate receptors, and their mRNA expression, since they are responsive to chronic modafinil and METH treatment. Acute modafinil and METH injections caused similar effects on total histone acetylation, increasing H3ac and decreasing H4ac, and they also increased HDAC1, HDAC2 and GluN1 protein levels in the mouse mPFC. In addition, the effects of the drugs were prevented by pre-treatment with D1Rs and D2Rs antagonists. Specifically, the changes in H4ac, HDAC2, and GluN1 were responsive to SCH23390, whereas those of H3ac and GluN1 were responsive to raclopride. Whole-cell patch clamp in transgenic BAC-Drd1a-tdTomato mice showed that METH, but not modafinil, induced paired-pulse facilitation of EPSCs, suggesting reduced presynaptic probability of glutamate release onto layer V pyramidal neurons. Analysis of histone 3/4 enrichment at specific promoters revealed: i) distinct effects of the drugs on histone 3 acetylation, with modafinil increasing H3ac at Drd1 and Adra1b promoters, but METH increasing H3ac at Adra1a; ii) distinct effects on histone 4 acetylation enrichment, with modafinil increasing H4ac at the Drd2 promoter and decreasing it at Hrh1, but METH increasing H4ac at Drd1; iii) comparable effects of both psychostimulants, increasing H3ac at Drd2, Hcrtr1, and Hrh1 promoters, decreasing H3ac at Hrh3, increasing H4ac at Hcrtr1, and decreasing H4ac at Hcrtr2, Hrh3, and Grin1 promoters. Interestingly, only METH altered mRNA levels of genes with altered histone acetylation status, inducing increased expression of Drd1a, Adra1a, Hcrtr1, and Hrh1, and decreasing Grin1. Our study suggests that although acute METH and modafinil can both increase DA neurotransmission in the mPFC, there are similar and contrasting epigenetic and transcriptional consequences that may account for their divergent clinical effects.

2018-03-01·Progress in Neuro-Psychopharmacology and Biological Psychiatry

Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA methylation profiles in the mouse medial prefrontal cortex

Article

作者: Jayanthi, Subramaniam ; Sosa, Máximo H ; Bisagno, Verónica ; Urbano, Francisco J ; García-Rill, Edgar ; González, Betina ; Torres, Oscar V ; Bernardi, Alejandra ; Gomez, Natalia ; Cadet, Jean-Lud

Methamphetamine (METH) and modafinil are psychostimulants with different long-term cognitive profiles: METH is addictive and leads to cognitive decline, whereas modafinil has little abuse liability and is a cognitive enhancer. Increasing evidence implicates epigenetic mechanisms of gene regulation behind the lasting changes that drugs of abuse and other psychotropic compounds induce in the brain, like the control of gene expression by histones 3 and 4 tails acetylation (H3ac and H4ac) and DNA cytosine methylation (5-mC). Mice were treated with a seven-day repeated METH, modafinil or vehicle protocol and evaluated in the novel object recognition (NOR) test or sacrificed 4days after last injection for molecular assays. We evaluated total H3ac, H4ac and 5-mC levels in the medial prefrontal cortex (mPFC), H3ac and H4ac promotor enrichment (ChIP) and mRNA expression (RT-PCR) of neurotransmitter systems involved in arousal, wakefulness and cognitive control, like dopaminergic (Drd1 and Drd2), α-adrenergic (Adra1a and Adra1b), orexinergic (Hcrtr1 and Hcrtr2), histaminergic (Hrh1 and Hrh3) and glutamatergic (AMPA Gria1 and NMDA Grin1) receptors. Repeated METH and modafinil treatment elicited different cognitive outcomes in the NOR test, where modafinil-treated mice performed as controls and METH-treated mice showed impaired recognition memory. METH-treated mice also showed i) decreased levels of total H3ac and H4ac, and increased levels of 5-mC, ii) decreased H3ac enrichment at promoters of Drd2, Hcrtr1/2, Hrh1 and Grin1, and increased H4ac enrichment at Drd1, Hrh1 and Grin1, iii) increased mRNA of Drd1a, Grin1 and Gria1. Modafinil-treated mice shared none of these effects and showed increased H3ac enrichment and mRNA expression at Adra1b. Modafinil and METH showed similar effects linked to decreased H3ac in Hrh3, increased H4ac in Hcrtr1, and decreased mRNA expression of Hcrtr2. The specific METH-induced epigenetic and transcriptional changes described here may be related to the long-term cognitive decline effects of the drug and its detrimental effects on mPFC function. The lack of similar epigenetic effects of chronic modafinil administration supports this notion.