Chiral Cardiovascular Drugs

Ranade, Vasant; Somberg, John C.

doi:10.1097/01.mjt.0000167429.37357.0c

Cited by 22 publications

(23 citation statements)

References 77 publications

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“…The S(+)enantiomer of nilvadipine is also about 100 times more potent in relaxing potassium-induced contractions of isolated dog coronary arteries than the R(-)-enantiomer 156 . A similar effect is observed in the case of amlodipine, where S-enantiomer is potent 151 . Species or sex-dependent stereoselective disposition of several dihydropyridines such as: nilvadipine in rats, dogs, and humans, felodipine in rats, dogs, and humans, and lemildipine in rats has been also observed, while negligible species and sex differences have been found for nisoldipine in dogs, rats, and mice.…”

Section: Pharmacodynamics and Pharmacokineticssupporting

confidence: 71%

“…RR-isomer is responsible for beta-blocking activity and SR-isomer is responsible for alpha-blocking activity. On the other hand RS-and SS-isomers display weak antagonistic activities against alpha and beta-receptors 150,151 .…”

Section: Pharmacodynamics and Pharmacokineticsmentioning

confidence: 99%

“…Metabolism of verapamil (Fig. 18) is stereoselective and favours the more active S(-)-enantiomer 97,151,157 .…”

Section: Pharmacodynamics and Pharmacokineticsmentioning

confidence: 99%

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Pharmacologically active compounds in the environment and their chirality

2010

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Pharmacologically active compounds including both legally used pharmaceuticals and illicit drugs are potent environmental contaminants. Extensive research has been undertaken over the recent years to understand their environmental fate and toxicity. The one very important phenomenon that has been overlooked by environmental researchers studying the fate of pharmacologically active compounds in the environment is their chirality. Chiral drugs can exist in the form of enantiomers, which have similar physicochemical properties but differ in their biological properties such as distribution, metabolism and excretion, as these processes (due to stereospecific interactions of enantiomers with biological systems) usually favour one enantiomer over the other. Additionally, due to different pharmacological activity, enantiomers of chiral drugs can differ in toxicity. Furthermore, degradation of chiral drugs during wastewater treatment and in the environment can be stereoselective and can lead to chiral products of varied toxicity. The distribution of different enantiomers of the same chiral drug in the aquatic environment and biota can also be stereoselective. Biological processes can lead to stereoselective enrichment or depletion of the enantiomeric composition of chiral drugs. As a result the very same drug might reveal different activity and toxicity and this will depend on its origin and exposure to several factors governing its fate in the environment. In this critical review a discussion of the importance of chirality of pharmacologically active compounds in the environmental context is undertaken and suggestions for directions in further research are made. Several groups of chiral drugs of major environmental relevance are discussed and their pharmacological action and disposition in the body is also outlined as it is a key factor in developing a full understanding of their environmental occurrence, fate and toxicity. This review will be of interest to environmental scientists, especially those interested in issues associated with environmental contamination with pharmacologically active compounds and chiral pollutants. As the review will outline current state of knowledge on chiral drugs, it will be of value to anyone interested in the phenomenon of chirality, chiral drugs, their stereoselective disposition in the body and environmental fate (212 references).

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Section: Pharmacodynamics and Pharmacokineticssupporting

confidence: 71%

Section: Pharmacodynamics and Pharmacokineticsmentioning

confidence: 99%

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Pharmacologically active compounds in the environment and their chirality

2010

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“…Interestingly, Car is one of three agents currently approved for the treatment of heart failure (36), and may possess a survival advantage over other ␤AR antagonists (40). Although Alp is used in the treatment of hypertension, angina, and arrhythmia (41)(42)(43), its clinical efficacy in treating heart failure remains to be tested.…”

Section: Discussionmentioning

confidence: 99%

β-Blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation

Kim¹,

Tilley²,

Chen³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

249

254

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Recent evidence suggests that binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also ␤-arrestin-dependent signaling. One such ␤-arrestin-mediated pathway uses the ␤1-adrenergic receptor (␤1AR) to transactivate the EGFR. To determine whether ␤-adrenergic ligands that do not activate G protein signaling (i.e., ␤-blockers) can stabilize the ␤1AR in a signaling conformation, we screened 20 ␤-blockers for their ability to stimulate ␤-arrestin-mediated EGFR transactivation. Here we show that only alprenolol (Alp) and carvedilol (Car) induce ␤1AR-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the ␤1AR lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against ␤-arrestin, we show that Alp-and Car-stimulated EGFR transactivation requires ␤1AR phosphorylation at consensus G protein-coupled receptor kinase sites and ␤-arrestin recruitment to the ligand-occupied receptor. Moreover, pharmacological inhibition of Src and EGFR blocked Alp-and Car-stimulated EGFR transactivation. Our findings demonstrate that Alp and Car are ligands that not only act as classical receptor antagonists, but can also stimulate signaling pathways in a G protein-independent, ␤-arrestin-dependent fashion.␤-adrenergic receptor ͉ G protein-coupled receptor ͉ signaling

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“…This practice represents a major limitation, as data on the important role of stereochemical properties of flavanols with regard to their absorption, metabolism, and bioactivity in humans and animals are accumulating (Baba et al, 2001;Donovan et al, 2006;Ritter et al, 2010). That flavanol stereoisomers can have markedly different bioactivities should not be a surprise given the well recognized importance of stereochemical properties with regards to the bioavailability and bioactivity of many essential macro-nutrients, vitamins, and drugs (Blatt et al, 2004;Brocks, 2006;Clifford et al, 2006;Ranade and Somberg, 2005). Thus, considering flavanol stereochemistry in the context of food intake assessments and dietary interventions would be impactful, as agricultural processes, food manufacture, and food preparation can greatly affect the stereo-specific flavanol content and profile of the food/beverage that is ultimately consumed (Gotti et al, 2006;Kodama et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Recommending flavanols and procyanidins for cardiovascular health: Current knowledge and future needs

Schroeter

Heiß

Spencer

et al. 2010

Molecular Aspects of Medicine

110

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Data on the potential health benefits of dietary flavanols and procyanidins, especially in the context of cardiovascular health, are considerable and continue to accumulate. Significant progress has been made in flavanol analytics and the creation of phytonutrient-content food databases, and novel data emanated from epidemiological investigations as well as dietary intervention studies. However, a comprehensive understanding of the pharmacological properties of flavanols and procyanidins, including their precise mechanisms of action in vivo, and a conclusive, consensus-based accreditation of a causal relationship between intake and health benefits in the context of primary and secondary cardiovascular disease prevention is still outstanding. Thus, the objective of this review is to identify and discuss key questions and gaps that will need to be addressed in order to conclusively demonstrate whether or not dietary flavanols and procyanidins have a role in preventing, delaying the onset of, or treating cardiovascular diseases, and thus improving human life expectancy and quality of life.

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Chiral Cardiovascular Drugs

Cited by 22 publications

References 77 publications

Pharmacologically active compounds in the environment and their chirality

Pharmacologically active compounds in the environment and their chirality

β-Blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation

Recommending flavanols and procyanidins for cardiovascular health: Current knowledge and future needs

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