Stereoselective binding of mexiletine and ketoprofen enantiomers with human serum albumin domains

Shi, Da; Jin, Yin-Xiu; Tang, Yanhui; Xu, Siyun; Yu, Lushan; Jiang, Huidi; Zeng, Su

doi:10.1038/aps.2012.8

Cited by 10 publications

(8 citation statements)

References 32 publications

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“…In particular, the (R)-enantiomer presented a downfield sense of the 1 H NMR signal non-equivalence, in agreement with what observed for the other studied mexiletine analogues [32]. Actually, recent studies showed that the binding of mexiletine enantiomers to human serum proteins was enantioselective [33,34]. Herein, we synthesized nonracemic MHM enantiomers as tools that can be used to study the enantioselectivity of this class of voltage-gated sodium channel blockers.…”

Section: Resultssupporting

confidence: 84%

Stereospecific Synthesis of m-Hydroxymexiletine Enantiomers

Catalano

Carocci²,

Lentini³

et al. 2013

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m-Hydroxymexiletine (MHM) is a metabolite of mexiletine, a well known class IB anti-arrhythmic drug, which presents almost twice the activity of the parent compound on cardiac voltage-gated sodium channels. Given the different activity of mexiletine enantiomers on sodium currents (being the R-isomer the eutomer), it is conceivable that (R)- and(S)-MHM could differ in pharmacodynamic and pharmacokinetic properties, too. Herein we report the efficient synthesis of MHM enantiomers that could represent useful tools for further investigations on stereospecific requirements of the voltage-gated sodium channel binding site. MHM enantiomers and all the homochiral intermediates were fully characterized. The ee values for (R)- and (S)-MHM were >99%, as assessed by capillary electrophoresis using β-cyclodextrin sulfated sodium salt as a chiral selector.

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Section: Resultssupporting

confidence: 84%

Stereospecific Synthesis of m-Hydroxymexiletine Enantiomers

Catalano

Carocci²,

Lentini³

et al. 2013

DML

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“…To study the accurate localization of ketoprofen and mexiletine binding sites on HSA, Shi et al 95 produced three highly purified recombinant HSA domains, each of which had a specific ligand binding site. They found that HSA DOM III possessed the chiral recognition ability for the ketoprofen enantiomers, whereas HSA DOM II recognized the mexiletine enantiomers.…”

Section: Stereoselectivity Of Plasma Protein Binding To Chiral Drugsmentioning

confidence: 99%

Stereoselective binding of chiral drugs to plasma proteins

et al. 2013

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Chiral drugs show distinct biochemical and pharmacological behaviors in the human body. The binding of chiral drugs to plasma proteins usually exhibits stereoselectivity, which has a far-reaching influence on their pharmacological activities and pharmacokinetic profiles. In this review, the stereoselective binding of chiral drugs to human serum albumin (HSA), α1-acid glycoprotein (AGP) and lipoprotein, three most important proteins in human plasma, are detailed. Furthermore, the application of AGP variants and recombinant fragments of HSA for studying enantiomer binding properties is also discussed. Apart from the stereoselectivity of enantiomer-protein binding, enantiomer-enantiomer interactions that may induce allosteric effects are also described. Additionally, the techniques and methods used to determine drug-protein binding parameters are briefly reviewed.

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“…Consequently, increasing more attention was paid on the molecular mechanisms involved in enantioselective discrimination by HSA. For instance, investigations have shown that enantiomers of warfarin, catechin, ketoprofen, ibuprofen and metalaxyl behave significantly different in pharmacokinetics and interaction with HSA [10][11][12][13][14]. As mentioned above, enantioselectivity in protein binding assessment is a momentous part in the biodistribution of chiral ligands, whereas such consequences cannot be obtained from achiral analysis.…”

Section: Introductionmentioning

confidence: 99%