プロプラノロール
概要
説明
プロプラノロールは、1962年に特許を取得し、1964年に医療用として承認されました 。プロプラノロールは、高血圧、狭心症、不整脈などの様々な心臓血管疾患の治療に広く用いられています。 さらに、不安、片頭痛予防、本態性振戦の管理にも用いられています .
2. 製法
プロプラノロールは、いくつかの合成経路を経て合成することができます。一般的な方法の1つは、ナフトールとエピクロロヒドリンを反応させて3-(1-ナフチロキシ)-1,2-エポキシプロパンを生成することです。 この中間体は、次にイソプロピルアミンと反応してプロプラノロールを生成します 。 この反応は、通常、相間移動触媒とアルカリ性媒体を必要とし、プロセスを促進します 。 工業的生産方法は、多くの場合、同様のステップを含みますが、大規模合成に最適化されており、高収率と高純度が確保されています .
科学的研究の応用
Propranolol has a wide range of scientific research applications:
作用機序
生化学分析
Biochemical Properties
Propranolol plays a significant role in biochemical reactions by interacting with various enzymes, proteins, and other biomolecules. It primarily binds to beta-adrenergic receptors, inhibiting the action of catecholamines like adrenaline and noradrenaline. This interaction leads to a decrease in cyclic adenosine monophosphate (cAMP) levels, which in turn reduces the activity of protein kinase A (PKA). Propranolol also interacts with cytochrome P450 enzymes, particularly CYP2D6 and CYP1A2, which are involved in its metabolism .
Cellular Effects
Propranolol exerts various effects on different types of cells and cellular processes. In cardiac cells, it reduces heart rate and contractility by blocking beta-adrenergic receptors, leading to decreased calcium influx. In neuronal cells, propranolol can cross the blood-brain barrier and influence neurotransmitter release, thereby reducing anxiety and preventing migraines. Additionally, propranolol affects cell signaling pathways by inhibiting the cAMP-PKA pathway, which impacts gene expression and cellular metabolism .
Molecular Mechanism
The molecular mechanism of propranolol involves its binding to beta-adrenergic receptors, which prevents the activation of these receptors by catecholamines. This inhibition leads to a decrease in cAMP levels and subsequent reduction in PKA activity. Propranolol also inhibits the activity of certain cytochrome P450 enzymes, affecting its own metabolism and the metabolism of other drugs. Furthermore, propranolol can modulate gene expression by influencing transcription factors and other regulatory proteins .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of propranolol change over time due to its stability and degradation. Propranolol is relatively stable under physiological conditions, but it can undergo degradation in the presence of light and heat. Long-term studies have shown that propranolol can have sustained effects on cellular function, including prolonged inhibition of beta-adrenergic receptors and persistent changes in gene expression. These effects are observed in both in vitro and in vivo studies .
Dosage Effects in Animal Models
The effects of propranolol vary with different dosages in animal models. At low doses, propranolol effectively reduces heart rate and blood pressure without significant adverse effects. At higher doses, propranolol can cause bradycardia, hypotension, and other toxic effects. Threshold effects have been observed, where a certain dosage is required to achieve the desired therapeutic effect. In animal studies, propranolol has been shown to affect various physiological parameters, including heart rate, blood pressure, and metabolic rate .
Metabolic Pathways
Propranolol is metabolized primarily in the liver through three main pathways: aromatic hydroxylation, N-dealkylation, and direct glucuronidation. The enzymes involved in these pathways include CYP2D6 and CYP1A2. The primary metabolites of propranolol are propranolol glucuronide, naphthyloxylactic acid, and sulfate and glucuronic acid conjugates of 4-hydroxy propranolol. These metabolites possess varying degrees of beta-adrenergic receptor blocking activity and can influence the overall pharmacological effects of propranolol .
Transport and Distribution
Propranolol is transported and distributed within cells and tissues through various mechanisms. It is highly lipophilic, allowing it to cross cell membranes easily and accumulate in tissues with high lipid content, such as the brain and adipose tissue. Propranolol is also transported by specific binding proteins and transporters, which facilitate its distribution within the body. The localization and accumulation of propranolol can affect its therapeutic efficacy and potential side effects .
Subcellular Localization
The subcellular localization of propranolol is influenced by its lipophilicity and interactions with cellular components. Propranolol can localize to various subcellular compartments, including the plasma membrane, mitochondria, and endoplasmic reticulum. Its activity and function can be affected by post-translational modifications and targeting signals that direct it to specific organelles. The subcellular localization of propranolol plays a crucial role in its overall pharmacological effects and therapeutic outcomes .
準備方法
Propranolol can be synthesized through several synthetic routes. One common method involves the reaction of naphthol with epichlorohydrin to form 3-(1-naphthyloxy)-1,2-epoxypropane. This intermediate is then reacted with isopropylamine to yield propranolol . The reaction typically requires a phase transfer catalyst and an alkaline medium to facilitate the process . Industrial production methods often involve similar steps but are optimized for large-scale synthesis, ensuring high yield and purity .
化学反応の分析
プロプラノロールは、以下の化学反応を含む様々な化学反応を起こします。
酸化： プロプラノロールは、酸化されて主要な代謝物である4'-ヒドロキシプロプラノロールを生成することができます.
還元： 還元反応はあまり一般的ではありませんが、特定の条件下で起こる可能性があります。
これらの反応で用いられる一般的な試薬には、過マンガン酸カリウムなどの酸化剤、水素化ホウ素ナトリウムなどの還元剤、メトキシドナトリウムなどの求核剤が含まれます 。生成される主要な生成物は、反応条件と用いられる試薬によって異なります。
4. 科学研究への応用
プロプラノロールは、様々な科学研究に応用されています。
類似化合物との比較
プロプラノロールは、メトプロロール、アテノロール、チモロールなどの他のベータ遮断薬と比較されます。
メトプロロール： プロプラノロールとは異なり、メトプロロールは選択的なβ1アドレナリン受容体拮抗薬であり、呼吸器疾患のある患者に適しています.
アテノロール： メトプロロールと同様に、アテノロールはβ1受容体に選択的ですが、プロプラノロールよりも半減期が長くなっています.
チモロール： チモロールは、プロプラノロールのように非選択的ですが、緑内障治療のための眼科用製剤によく用いられています.
プロプラノロールは、非選択的で血液脳関門を通過できるというユニークな特性を持ち、心臓血管疾患と中枢神経系の両方の状態に効果があります .
特性
IUPAC Name |
1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C16H21NO2/c1-12(2)17-10-14(18)11-19-16-9-5-7-13-6-3-4-8-15(13)16/h3-9,12,14,17-18H,10-11H2,1-2H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
AQHHHDLHHXJYJD-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C)NCC(COC1=CC=CC2=CC=CC=C21)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C16H21NO2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID6023525 |
Source
|
| Record name | Propranolol | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6023525 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
259.34 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Propranolol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001849 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
0.0617 mg/L at 25 °C |
Source
|
| Record name | Propranolol | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00571 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Propranolol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001849 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Propranolol is a nonselective β-adrenergic receptor antagonist. Blocking of these receptors leads to vasoconstriction, inhibition of angiogenic factors like vascular endothelial growth factor (VEGF) and basic growth factor of fibroblasts (bFGF), induction of apoptosis of endothelial cells, as well as down regulation of the renin-angiotensin-aldosterone system. |
Source
|
| Record name | Propranolol | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00571 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
CAS No. |
525-66-6, 13013-17-7 |
Source
|
| Record name | Propranolol | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=525-66-6 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | racemic-Propranolol | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000525666 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Propranolol | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00571 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Propranolol | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6023525 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | (±)-1-(isopropylamino)-3-(naphthyloxy)propan-2-ol | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.032.592 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | Propranolol | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.007.618 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | PROPRANOLOL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/9Y8NXQ24VQ | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | Propranolol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001849 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
96 °C |
Source
|
| Record name | Propranolol | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00571 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Propranolol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001849 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
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Retrosynthesis Analysis
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Strategy Settings
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| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
試験管内研究製品の免責事項と情報
BenchChemで提示されるすべての記事および製品情報は、情報提供を目的としています。BenchChemで購入可能な製品は、生体外研究のために特別に設計されています。生体外研究は、ラテン語の "in glass" に由来し、生物体の外で行われる実験を指します。これらの製品は医薬品または薬として分類されておらず、FDAから任何の医療状態、病気、または疾患の予防、治療、または治癒のために承認されていません。これらの製品を人間または動物に体内に導入する形態は、法律により厳格に禁止されています。これらのガイドラインに従うことは、研究と実験において法的および倫理的な基準の遵守を確実にするために重要です。
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