Bromocriptine
Descripción general
Descripción
La bromocriptina es un derivado de la ergolina y un agonista de la dopamina. Originalmente se comercializó con el nombre de marca Parlodel y desde entonces se ha vendido bajo varios otros nombres. La bromocriptina se utiliza principalmente en el tratamiento de tumores de la hipófisis, enfermedad de Parkinson, hiperprolactinemia, síndrome neuroléptico maligno y diabetes tipo 2 . Fue patentada en 1968 y aprobada para uso médico en 1975 .
Mecanismo De Acción
La bromocriptina ejerce sus efectos actuando como un agonista del receptor D2 de la dopamina. Se une a los receptores de dopamina en el cerebro, inhibiendo la liberación de prolactina de la glándula pituitaria. Este mecanismo es beneficioso para tratar afecciones como la hiperprolactinemia y la enfermedad de Parkinson. En el caso de la diabetes tipo 2, la bromocriptina ayuda a mejorar el control glucémico al aumentar los niveles de dopamina hipotalámica, lo que a su vez reduce la resistencia a la insulina y la producción de glucosa hepática .
Compuestos similares:
Cabergolina: Otro agonista de la dopamina que se utiliza para tratar la hiperprolactinemia y la enfermedad de Parkinson.
Pergolida: Utilizado en el tratamiento de la enfermedad de Parkinson.
Quinagolida: Un agonista de la dopamina no ergolínico que se utiliza para tratar la hiperprolactinemia.
Comparación: La bromocriptina es única en su formulación de liberación rápida, que permite una rápida aparición de la acción. También se utiliza como terapia adyuvante para la diabetes tipo 2, una característica que no se observa comúnmente con otros agonistas de la dopamina. La cabergolina, por otro lado, tiene una vida media más larga y a menudo se prefiere por su régimen de dosificación menos frecuente .
Análisis Bioquímico
Biochemical Properties
Bromocriptine is a partial agonist of the dopamine D2 receptor . It also interacts with other dopamine receptors and with various serotonin and adrenergic receptors . This compound has additionally been found to inhibit the release of glutamate by reversing the GLT1 glutamate transporter .
Cellular Effects
This compound blocks the release of a hormone called prolactin from the pituitary gland . Prolactin affects the menstrual cycle and milk production . This compound is used to treat certain menstrual problems in women and stops milk production in some men and women who have abnormal milk leakage .
Molecular Mechanism
This compound stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects . Five dopamine receptor types from two dopaminergic subfamilies have been identified . The dopaminergic D1 receptor subfamily consists of D1 and D5 subreceptors, which are associated with dyskinesias .
Temporal Effects in Laboratory Settings
In laboratory settings, this compound use was associated with a modest but statistically significant decline in temperature, with nadir at 72 h post initiation . This suggests that the effects of this compound can change over time in a laboratory setting.
Dosage Effects in Animal Models
In animal models, studies conducted on this compound have shown that stimulating D2 receptors may enhance working memory in rodents, whereas inhibiting these receptors could have the opposite effect, reducing working memory performance .
Metabolic Pathways
This compound is completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic . This compound is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion .
Transport and Distribution
This compound is rapidly absorbed (about 28% to 37% of the total dose) after oral administration . It is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion .
Métodos De Preparación
Rutas sintéticas y condiciones de reacción: La bromocriptina se sintetiza a través de una serie de reacciones químicas que comienzan con alcaloides del cornezuelo de centeno. La preparación de mesilato de bromocriptina implica disolver la bromocriptina en metanol, seguido de la adición de una solución acuosa de ácido metanosulfónico. La mezcla se agita, enfría, filtra y recristaliza con etanol para obtener mesilato de bromocriptina .
Métodos de producción industrial: La producción industrial de bromocriptina sigue pasos similares, pero a mayor escala. El proceso implica un control preciso de las condiciones de reacción, como la temperatura y el pH, para garantizar un alto rendimiento y pureza del producto final .
Análisis De Reacciones Químicas
Tipos de reacciones: La bromocriptina sufre varias reacciones químicas, que incluyen:
Oxidación: La bromocriptina se puede oxidar en condiciones específicas para formar diferentes metabolitos.
Reducción: Las reacciones de reducción pueden modificar el átomo de bromo en la molécula.
Reactivos y condiciones comunes:
Oxidación: Los agentes oxidantes comunes incluyen permanganato de potasio y peróxido de hidrógeno.
Reducción: Se pueden utilizar agentes reductores como el hidruro de aluminio y litio.
Sustitución: Las reacciones de intercambio de halógenos se pueden llevar a cabo utilizando reactivos como el yoduro de sodio.
Productos principales: Los productos principales formados a partir de estas reacciones dependen de las condiciones y los reactivos específicos utilizados. Por ejemplo, la oxidación puede conducir a la formación de varios metabolitos hidroxilados .
Aplicaciones Científicas De Investigación
La bromocriptina tiene una amplia gama de aplicaciones de investigación científica:
Biología: La bromocriptina se utiliza para estudiar las funciones de los receptores de dopamina y las vías de señalización.
Medicina: Se utiliza ampliamente en el tratamiento de afecciones como la hiperprolactinemia, la enfermedad de Parkinson y la diabetes tipo 2
Comparación Con Compuestos Similares
Cabergoline: Another dopamine agonist used to treat hyperprolactinemia and Parkinson’s disease.
Pergolide: Used in the treatment of Parkinson’s disease.
Quinagolide: A non-ergoline dopamine agonist used to treat hyperprolactinemia.
Comparison: Bromocriptine is unique in its quick-release formulation, which allows for rapid onset of action. It is also used as an adjunct therapy for type 2 diabetes, a feature not commonly seen with other dopamine agonists. Cabergoline, on the other hand, has a longer half-life and is often preferred for its less frequent dosing schedule .
Propiedades
IUPAC Name |
(6aR,9R)-5-bromo-N-[(1S,2S,4R,7S)-2-hydroxy-7-(2-methylpropyl)-5,8-dioxo-4-propan-2-yl-3-oxa-6,9-diazatricyclo[7.3.0.02,6]dodecan-4-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C32H40BrN5O5/c1-16(2)12-24-29(40)37-11-7-10-25(37)32(42)38(24)30(41)31(43-32,17(3)4)35-28(39)18-13-20-19-8-6-9-22-26(19)21(27(33)34-22)14-23(20)36(5)15-18/h6,8-9,13,16-18,23-25,34,42H,7,10-12,14-15H2,1-5H3,(H,35,39)/t18-,23-,24+,25+,31-,32+/m1/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
OZVBMTJYIDMWIL-AYFBDAFISA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C)CC1C(=O)N2CCCC2C3(N1C(=O)C(O3)(C(C)C)NC(=O)C4CN(C5CC6=C(NC7=CC=CC(=C67)C5=C4)Br)C)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]3(N1C(=O)[C@](O3)(C(C)C)NC(=O)[C@H]4CN([C@@H]5CC6=C(NC7=CC=CC(=C67)C5=C4)Br)C)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C32H40BrN5O5 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
22260-51-1 (mesylate (salt)) |
Source
|
| Record name | Bromocriptine [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0025614033 | |
| 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. | |
DSSTOX Substance ID |
DTXSID1022687 |
Source
|
| Record name | Bromocriptine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID1022687 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
654.6 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 | Bromocriptine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015331 | |
| 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 |
8.58e-02 g/L |
Source
|
| Record name | Bromocriptine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015331 | |
| 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 |
The dopamine D2 receptor is a 7-transmembrane G-protein coupled receptor associated with Gi proteins. In lactotrophs, stimulation of dopamine D2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca2+ from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. |
Source
|
| Record name | Bromocriptine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01200 | |
| 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. |
25614-03-3 |
Source
|
| Record name | (+)-Bromocriptine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=25614-03-3 | |
| 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 | Bromocriptine [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0025614033 | |
| 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 | Bromocriptine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01200 | |
| 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 | Bromocriptine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID1022687 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Bromocriptine | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.042.829 | |
| 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 | BROMOCRIPTINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/3A64E3G5ZO | |
| 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 | Bromocriptine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015331 | |
| 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 |
215-218 |
Source
|
| Record name | Bromocriptine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01200 | |
| 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) | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| 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
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