Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis

Cizmáriková, R; Valentová, Jindra; Horáková, Renáta

doi:10.1515/chem-2020-0056

Cited by 12 publications

(6 citation statements)

References 153 publications

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“…Here, we tested numerous chiral inhibitors from different drug classes for stereoselective differences of OCT inhibition. In contrast to drug membrane transporters, stereoselectivity is a well-studied feature in receptor binding and drug metabolism. − …”

Section: Discussionmentioning

confidence: 99%

Stereoselective Inhibition of High- and Low-Affinity Organic Cation Transporters

Gebauer,

Jensen,

Rafehi

et al. 2023

Mol. Pharmaceutics

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Many drugs have chiral centers and are therapeutically applied as racemates. Thus, the stereoselectivity in their interactions with membrane transporters needs to be addressed. Here, we studied stereoselectivity in inhibiting organic cation transporters (OCTs) 1, 2, and 3 and the high-affinity monoamine transporters (MATs) NET and SERT. Selectivity by the inhibition of 35 pairs of enantiomers significantly varied among the three closely related OCTs. OCT1 inhibition was nonselective in almost all cases, whereas OCT2 was stereoselectively inhibited by 45% of the analyzed drugs. However, the stereoselectivity of the OCT2 was only moderate with the highest selectivity observed for pramipexole. The (R)-enantiomer inhibited OCT2 4-fold more than the (S)-enantiomer. OCT3 showed the greatest stereoselectivity in its inhibition. (R)-Tolterodine and (S)-zolmitriptan inhibited OCT3 11-fold and 25-fold more than their respective counterparts. Interestingly, in most cases, the pharmacodynamically active enantiomer was also the stronger OCT inhibitor. In addition, stereoselectivity in the OCT inhibition appeared not to depend on the transported substrate. For high-affinity MATs, our data confirmed the stereoselective inhibition of NET and SERT by several antidepressants. However, the stereoselectivity measured here was generally lower than that reported in the literature. Unexpectedly, the high-affinity MATs were not significantly more stereoselectively inhibited than the polyspecific OCTs. Combining our in vitro OCT inhibition data with available stereoselective pharmacokinetic analyses revealed different risks of drug–drug interactions, especially at OCT2. For the tricyclic antidepressant doxepine, only the (E)-isomer showed an increased risk of drug–drug interactions according to guidelines from regulatory authorities for renal transporters. However, most chiral drugs show only minor stereoselectivity in the inhibition of OCTs in vitro, which is unlikely to translate into clinical consequences.

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Section: Discussionmentioning

confidence: 99%

Stereoselective Inhibition of High- and Low-Affinity Organic Cation Transporters

Gebauer,

Jensen,

Rafehi

et al. 2023

Mol. Pharmaceutics

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“…The differential pharmacodynamic and toxicological properties of the enantiomers of chiral drugs have been known for a number of years, affecting essentially all categories of drugs [ 47 , 48 , 49 , 50 , 51 ]. At one extreme, one enantiomer may be devoid of any biological activity; at the other extreme, both enantiomers may exhibit qualitatively different biological activities.…”

Section: Chirality In Drug Designmentioning

confidence: 99%

Analogues of Anticancer Natural Products: Chiral Aspects

Valentová

Lintnerová

Miklášova

et al. 2023

IJMS

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Life is chiral, as its constituents consist, to a large degree, of optically active molecules, be they macromolecules (proteins, nucleic acids) or small biomolecules. Hence, these molecules interact disparately with different enantiomers of chiral compounds, creating a preference for a particular enantiomer. This chiral discrimination is of special importance in medicinal chemistry, since many pharmacologically active compounds are used as racemates—equimolar mixtures of two enantiomers. Each of these enantiomers may express different behaviour in terms of pharmacodynamics, pharmacokinetics, and toxicity. The application of only one enantiomer may improve the bioactivity of a drug, as well as reduce the incidence and intensity of adverse effects. This is of special significance regarding the structure of natural products since the great majority of these compounds contain one or several chiral centres. In the present survey, we discuss the impact of chirality on anticancer chemotherapy and highlight the recent developments in this area. Particular attention has been given to synthetic derivatives of drugs of natural origin, as naturally occurring compounds constitute a major pool of new pharmacological leads. Studies have been selected which report the differential activity of the enantiomers or the activities of a single enantiomer and the racemate.

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“…18 Probably, these adverse effects may be a result of the (S)-(+)-terbutaline enantiomer which is less pharmaceutically. 10,11 Under such situations, the prescription of racemic terbutaline is not safe and the medicine should be resolved first into enantiomers before the optically pure drug isgiven to the patients. For these reasons and the pressure of rising costs, there is a great demand to develop fast and economic separation methods.…”

Section: Introductionmentioning

confidence: 99%

“…It is absorbed completely if administered orally 9 . It is proved that like other β 2 ‐agonists, ( R )‐(−)‐terbutaline is 200 times more active than ( S )‐(+)‐terbutaline 10,11 . Terbutaline has an asymmetric center at the α‐carbon and is generally prescribed and used as a racemate (Fig.…”

Section: Introductionmentioning

confidence: 99%

Chiral separation of terbutaline by supercritical fluid chromatography with peak purity determination by UPLC–MS and modeling for chiral recognition mechanism

Ali,

Alam,

Raja

et al. 2024

J of Chemical Tech & Biotech

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BackgroundTerbutaline is the drug of choice for asthma patients but it exist in racemic mixture. (R)‐(‐)‐terbutaline is 200 times more active than (S)‐(+)‐terbutaline and it is not advisable to prescribe racmix xiture due to certain side effects of (S)‐(+)‐terbutaline. Therefore, fast, effective and reproducible separation method is the need of today.ResultsChiral separation was achieved on Chiralpak IE and Chiralpak IG columns (250 mm x 4.6 mm, 5 μm) using CO2‐MeOH (60:40) with 0.2% triethylamine mobile phase. The flow was 1.0 mL/min with detection at 223 nm using a PDA detector. The values of retention, separation and resolution factors were in the range of 1.88 to 2.38, 1.14 to 1.26 and 0.91 to 1.17; with best separation with Chiralpak IE. The tailing factors and number of theoretical plates were in the range of 1.0 to 1.23 and 487 to 3699. The purity of the separated peaks was determined by UPLC‐MS; indicating 100% purity of the peaks. The chiral recognition was determined by modeling with binding affinities ‐5.0 and ‐6.0 of S‐ and R‐enantiomers; indicating S‐enantiomers elution first followed by R‐enantiomers. The major forces responsible for the chiral resolution were hydrogen bonding and π‐π interactions.ConclusionDue to the great demand for optically active pure drugs and high economic pressure on analytical techniques, the chiral separation of terbutaline was achieved on inexpensive supercritical fluid chromatography. The reported method may be used to prepare optically active pure terbutaline drugs (R‐enantiomers) at a pilot scale.This article is protected by copyright. All rights reserved.

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Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis

Cited by 12 publications

References 153 publications

Stereoselective Inhibition of High- and Low-Affinity Organic Cation Transporters

Stereoselective Inhibition of High- and Low-Affinity Organic Cation Transporters

Analogues of Anticancer Natural Products: Chiral Aspects

Chiral separation of terbutaline by supercritical fluid chromatography with peak purity determination by UPLC–MS and modeling for chiral recognition mechanism

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