Trihexyphenidyl
Descripción general
Descripción
El trihexifenidilo es un fármaco antiespasmódico sintético que se utiliza principalmente para controlar los síntomas de la enfermedad de Parkinson y las reacciones extrapiramidales inducidas por fármacos. Pertenece a la clase de medicamentos antimuscarínicos y es conocido por su capacidad para aliviar la rigidez, los temblores, los espasmos y la falta de control muscular . El trihexifenidilo fue aprobado por primera vez por la FDA en 1949 y desde entonces ha sido una herramienta valiosa en el tratamiento sintomático de diversas formas de parkinsonismo .
Métodos De Preparación
La síntesis de trihexifenidilo implica varios pasos clave:
Síntesis de la propofenona piperidil hidrocloruro intermedio: Este intermedio se prepara mediante la aminometilación de la acetofenona utilizando paraformaldehído y piperidina en una reacción de Mannich.
Formación de clorhidrato de trihexifenidilo bruto: El intermedio se hace reaccionar entonces con un reactivo de Grignard, utilizando normalmente éter metil terc-butílico como disolvente para evitar los problemas de seguridad asociados con el éter dietílico.
Refinamiento: El producto bruto se refina para obtener clorhidrato de trihexifenidilo puro.
Análisis De Reacciones Químicas
El trihexifenidilo experimenta diversas reacciones químicas, incluyendo:
Oxidación: Puede oxidarse en condiciones específicas, aunque esta no es una reacción común para su uso terapéutico.
Reducción: Las reacciones de reducción son menos comunes, pero se pueden realizar en condiciones de laboratorio controladas.
Sustitución: El trihexifenidilo puede experimentar reacciones de sustitución, particularmente involucrando su anillo de piperidina.
Los reactivos comunes utilizados en estas reacciones incluyen agentes oxidantes como el permanganato de potasio y agentes reductores como el hidruro de aluminio y litio. Los principales productos formados dependen de las condiciones de reacción específicas y de los reactivos utilizados.
Aplicaciones Científicas De Investigación
El trihexifenidilo tiene una amplia gama de aplicaciones de investigación científica:
Mecanismo De Acción
El trihexifenidilo ejerce sus efectos actuando como un antagonista no selectivo del receptor muscarínico de la acetilcolina, con mayor afinidad por el subtipo M1 . Inhibe el sistema nervioso parasimpático, lo que lleva a una reducción de la rigidez muscular y los temblores. El fármaco también tiene un efecto espasmolítico directo sobre el músculo liso y presenta efectos mióticos, antisialagógicos y bloqueadores cardiovagales débiles .
Comparación Con Compuestos Similares
El trihexifenidilo se compara a menudo con otros agentes anticolinérgicos, como:
Benztropina: Similar en sus efectos antimuscarínicos pero con diferentes propiedades farmacocinéticas.
Difenhidramina: Un antihistamínico con propiedades anticolinérgicas, utilizado para indicaciones similares pero con un rango más amplio de aplicaciones.
El trihexifenidilo es único por su afinidad específica por los receptores muscarínicos centrales, lo que lo hace particularmente efectivo para controlar los síntomas relacionados con el sistema nervioso central .
Propiedades
IUPAC Name |
1-cyclohexyl-1-phenyl-3-piperidin-1-ylpropan-1-ol |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C20H31NO/c22-20(18-10-4-1-5-11-18,19-12-6-2-7-13-19)14-17-21-15-8-3-9-16-21/h1,4-5,10-11,19,22H,2-3,6-9,12-17H2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
HWHLPVGTWGOCJO-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1CCC(CC1)C(CCN2CCCCC2)(C3=CC=CC=C3)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C20H31NO |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
52-49-3 (hydrochloride) |
Source
|
| Record name | Trihexyphenidyl [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000144116 | |
| 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 |
DTXSID4023705 |
Source
|
| Record name | Trihexyphenidyl | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID4023705 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
301.5 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 | Trihexyphenidyl | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014520 | |
| 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 |
Crystals; decomp at 258.5 °C; pH of 1% aq soln 5.5-6.0; solubility (g/100 mL): water at 25 °C 1.0, alcohol 6, chloroform 5; more soluble in methanol; very slightly soluble in ether, benzene /Hydrochloride/, 3.14e-03 g/L |
Source
|
| Record name | TRIHEXYPHENIDYL | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3196 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Trihexyphenidyl | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014520 | |
| 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 |
Trihexyphenidyl is a non-selective muscarinic acetylcholine receptor antagonist but binds with higher affinity to the M1 subtype. In vivo studies have shown that trihexyphenidyl demonstrates higher affinity for central muscarinic receptors located in the cerebral cortex and lower affinity for those located peripherally. Other studies suggest that trihexyphenidyl may modify nicotinic acetylcholine receptor neurotransmission, leading indirectly to enhanced dopamine release in the striatum. Although the anticholinergic has proven to be useful in the treatment of symptoms associated with Parkinson’s disease or other movement disorders, its mechanism of action has yet to be fully elucidated., Cerebral blood flow and oxygen metabolism were studied in six previously untreated patients with Parkinson's disease (PD) before and after anticholinergic treatment using positron emission tomography (PET) and compared with six controls. The PET study and an assessment of the disability and cognitive impairment were performed before and after administration of 6 mg trihexyphenidyl for 5 to 11 weeks. All PD patients showed improvements in motor symptoms after the trihexyphenidyl treatment. Cognitive function did not significantly differ between before and after trihexyphenidyl treatment. However, after trihexyphenidyl treatment, regional cerebral blood flow (rCBF) and regional oxygen metabolic rate (rCMRO2) decreased by 15% in the striatum and by 10% in all cortical areas contralateral to predominantly symptomatic limbs, and by 10% in the ipsilateral striatum and all cortical areas, significantly below the values of controls in most cerebral cortices and striatum. These findings suggest that trihexyphenidyl inhibits the cortical cholinergic system and significantly decreases rCBF and rCMRO2 in the cerebral cortices without cognitive impairment in untreated patients with PD., In common with other antimuscarinic agents, trihexyphenidyl produces an atropine-like blocking action on parasympathetic-innervated peripheral structures, including smooth muscle. In addition, trihexyphenidyl exhibits a direct spasmolytic action on smooth muscle and exhibits weak mydriatic, antisialagogue, and cardiovagal blocking effects. The exact mechanism of action of trihexyphenidyl in parkinsonian syndrome is not understood but may result from blockade of efferent impulses and from central inhibition of cerebral motor centers. In small doses, trihexyphenidyl depresses the CNS but larger doses cause cerebral excitement resembling the signs of atropine toxicity., In vivo microdialysis was used to study the effect of the non-selective muscarinic antagonist, trihexyphenidyl, on the decarboxylation of levodopa (L-dopa) in the striatum of hemi-Parkinson rats. In normal rats, continuous perfusion of trihexyphenidyl (1 mM) via the microdialysis probe induced a significant increase in striatal dopamine release, followed by a decrease to below baseline values. A similar effect was observed, though less pronounced, in denervated striatum of rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. In these hemi-Parkinson rats, continuous striatal perfusion of trihexyphenidyl had no effect on the biotransformation of locally applied L-dopa (2 uM for 20 min) to dopamine in either intact or denervated striatum. However, systemic administration of trihexyphenidyl (1.5 mg/kg ip) produced an attenuation of the L- dopa-induced dopamine release in the intact striatum (contralateral to the lesion) of hemi-Parkinson rats. This effect was absent in the denervated striatum of these animals. We confirmed that L-dopa induces an increase in striatal dopamine output which is influenced by the severity of the dopaminergic denervation. The absence of an effect of trihexyphenidyl locally applied in the striatum, on biotransformation of L-dopa suggests that the site of action of antimuscarinic drugs may not be in the striatum and, therefore, remains unclear. |
Source
|
| Record name | Trihexyphenidyl | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00376 | |
| 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 | TRIHEXYPHENIDYL | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3196 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Impurities |
1-phenyl-3-(piperidine-1-yl)propan-1-one |
Source
|
| Record name | TRIHEXYPHENIDYL | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3196 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
CAS No. |
144-11-6 |
Source
|
| Record name | (±)-Trihexyphenidyl | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=144-11-6 | |
| 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 | Trihexyphenidyl [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000144116 | |
| 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 | Trihexyphenidyl | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00376 | |
| 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 | trihexyphenidyl | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=12268 | |
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| Record name | Trihexyphenidyl | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID4023705 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Trihexyphenidyl | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.005.105 | |
| 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. | |
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| Record name | TRIHEXYPHENIDYL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/6RC5V8B7PO | |
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| 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 | TRIHEXYPHENIDYL | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3196 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Trihexyphenidyl | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014520 | |
| 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 |
114 °C, 258.5 °C |
Source
|
| Record name | Trihexyphenidyl | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00376 | |
| 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 | TRIHEXYPHENIDYL | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3196 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Trihexyphenidyl | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014520 | |
| 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. | |
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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