Advances in Development of Dopaminergic Aporphinoids

Zhang, Ao; Zhang, Yi; Branfman, Alan R.; Baldessarini, Ross J.; Neumeyer, John L.

doi:10.1002/chin.200719224

Cited by 12 publications

(43 citation statements)

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“…A wide spectrum of biological activities have been reported for all three alkaloids, and their core structures have been used to develop lead molecules for potential treatments against a variety of diseases (Zhang et al, 2007;Jadhav et al, 2010). For example, the protoberberine skeleton has been used to develop antibacterial agents (Jadhav et al, 2010), and bulbocapnine possesses dopamine D 2 receptor antagonist properties (Zhang et al, 2007). These three alkaloids are also present in several traditional Chinese medicine preparations (Salminen et al, 2011b).…”

Section: Discussionmentioning

confidence: 99%

“…Protopine is present, e.g., in preparations from the medicinal plant Fumaria officinalis, which is included in the European Pharmacopoeia (Vrba et al, 2011). A wide spectrum of biological activities have been reported for all three alkaloids, and their core structures have been used to develop lead molecules for potential treatments against a variety of diseases (Zhang et al, 2007;Jadhav et al, 2010). For example, the protoberberine skeleton has been used to develop antibacterial agents (Jadhav et al, 2010), and bulbocapnine possesses dopamine D 2 receptor antagonist properties (Zhang et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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CYP2C19 Progress Curve Analysis and Mechanism-Based Inactivation by Three Methylenedioxyphenyl Compounds

Salminen

Meyer²,

Imming³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Several in vitro criteria were used to assess whether three methylenedioxyphenyl (MDP) compounds, the isoquinoline alkaloids bulbocapnine, canadine, and protopine, are mechanism-based inactivators of CYP2C19. The recently reported fluorometric CYP2C19 progress curve analysis approach was applied first to determine whether these alkaloids demonstrate time-dependent inhibition. In this experiment, bulbocapnine, canadine, and proto- , respectively. Additional studies were performed to determine whether other specific criteria for mechanism-based inactivation were fulfilled: NADPH dependence, irreversibility, and involvement of a catalytic step in the enzyme inactivation. CYP2C19 activity was not significantly restored by dialysis when it had been inactivated by the alkaloids in the presence of a NADPH-regenerating system, and a metabolic-intermediate complex-associated increase in absorbance at approximately 455 nm was observed. In conclusion, the CYP2C19 progress curve analysis method revealed time-dependent inhibition by these alkaloids, and additional experiments confirmed its quasi-irreversible nature. This study revealed that the CYP2C19 progress curve analysis method is useful for identifying novel mechanism-based inactivators and yields a wealth of information in one run. The alkaloids bulbocapnine, canadine, and protopine, present in herbal medicines, are new mechanism-based inactivators and the first MDP compounds exhibiting quasi-irreversible inactivation of CYP2C19.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CYP2C19 Progress Curve Analysis and Mechanism-Based Inactivation by Three Methylenedioxyphenyl Compounds

Salminen

Meyer²,

Imming³

et al. 2011

Drug Metab Dispos

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“…Indeed, aporphines with an alpha C6a hydrogen such as bulbocapnine (CS 1.216), boldine, and glaucine are dopamine receptor antagonists, such as the dopaminergic receptor subtypes 1/2 (D 1 /D 2 ), 379,380 whereas the presence of a beta C6a hydrogen produces agonists, such as notably D 1 /D 2 . Indeed, aporphines with an alpha C6a hydrogen such as bulbocapnine (CS 1.216), boldine, and glaucine are dopamine receptor antagonists, such as the dopaminergic receptor subtypes 1/2 (D 1 /D 2 ), 379,380 whereas the presence of a beta C6a hydrogen produces agonists, such as notably D 1 /D 2 .…”

Section: Rationalementioning

confidence: 99%

Alkaloids

Wiart

2014

Lead Compounds From Medicinal Plants for the Treatment of Neurodegenerative Diseases

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“…Glaucine shows antitussive, bronchodilatory and anti‐inflammatory properties and acts also as weak dopamine D 1 and D 2 receptor antagonist . The antitussive properties of glaucine are comparable to codeine without signs of opiate withdrawal after longer intake . It is used as a therapeutic drug in Bulgaria and other countries as cough suppressant.…”

Section: Introductionmentioning

confidence: 99%

Studies on the metabolism and toxicological detection of glaucine, an isoquinoline alkaloid from Glaucium flavum (Papaveraceae), in rat urine using GC‐MS, LC‐MSⁿ and LC‐high‐resolution MSⁿ

Meyer

Wissenbach³

et al. 2013

J. Mass. Spectrom.

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Glaucine ((S)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-methyl-4H-dibenzo [de,g]quinoline) is an isoquinoline alkaloid and main component of Glaucium flavum (Papaveraceae). It was described to be consumed as recreational drug alone or in combination with other drugs. Besides this, glaucine is used as therapeutic drug in Bulgaria and other countries as cough suppressant. Currently, there are no data available concerning metabolism and toxicological analysis of glaucine. To study both, glaucine was orally administered to Wistar rats and urine was collected. For metabolism studies, work-up of urine samples consisted of protein precipitation or enzymatic cleavage followed by solid-phase extraction. Samples were afterwards measured by liquid chromatography (LC) coupled to low or high-resolution mass spectrometry (HR-MS). The phase I and II metabolites were identified by detailed interpretation of the corresponding fragmentations, which were further confirmed by determination of their elemental composition using HR-MS. From these data, the following metabolic pathways could be proposed: O-demethylation at position 2, 9 and 10, N-demethylation, hydroxylation, N-oxidation and combinations of them as well as glucuronidation and/or sulfation of the phenolic metabolites. For monitoring a glaucine intake in case of abuse or poisoning, the O- and N-demethylated metabolites were the main targets for the gas chromatography-MS and LC-MS(n) screening approaches described by the authors. Both allowed confirming an intake of glaucine in rat urine after a dose of 2 mg/kg body mass corresponding to a common abuser's dose.

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Advances in Development of Dopaminergic Aporphinoids

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 12 publications

References 1 publication

CYP2C19 Progress Curve Analysis and Mechanism-Based Inactivation by Three Methylenedioxyphenyl Compounds

CYP2C19 Progress Curve Analysis and Mechanism-Based Inactivation by Three Methylenedioxyphenyl Compounds

Alkaloids

Studies on the metabolism and toxicological detection of glaucine, an isoquinoline alkaloid from Glaucium flavum (Papaveraceae), in rat urine using GC‐MS, LC‐MSⁿ and LC‐high‐resolution MSⁿ

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Advances in Development of Dopaminergic Aporphinoids

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 12 publications

References 1 publication

CYP2C19 Progress Curve Analysis and Mechanism-Based Inactivation by Three Methylenedioxyphenyl Compounds

CYP2C19 Progress Curve Analysis and Mechanism-Based Inactivation by Three Methylenedioxyphenyl Compounds

Alkaloids

Studies on the metabolism and toxicological detection of glaucine, an isoquinoline alkaloid from Glaucium flavum (Papaveraceae), in rat urine using GC‐MS, LC‐MSn and LC‐high‐resolution MSn

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Product

Resources

About

Studies on the metabolism and toxicological detection of glaucine, an isoquinoline alkaloid from Glaucium flavum (Papaveraceae), in rat urine using GC‐MS, LC‐MSⁿ and LC‐high‐resolution MSⁿ