Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3
Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (...
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| Format: | Article |
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MDPI AG
2022-10-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/10/1507 |
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| author | Lukas Gebauer Muhammad Rafehi Jürgen Brockmöller |
| author_facet | Lukas Gebauer Muhammad Rafehi Jürgen Brockmöller |
| author_sort | Lukas Gebauer |
| collection | DOAJ |
| description | Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported <i>(S)</i>-norepinephrine, SERT preferred the <i>(R)</i>-enantiomer. In contrast, NET and DAT showed higher transport for <i>(R)</i>-epinephrine and SERT for <i>(S)</i>-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most <i>(R)</i>-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their <i>(R)</i>-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters. |
| first_indexed | 2024-03-09T20:36:46Z |
| format | Article |
| id | doaj.art-43607307b4ef4930b2a3070b816fb362 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T20:36:46Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-43607307b4ef4930b2a3070b816fb3622023-11-23T23:09:46ZengMDPI AGBiomolecules2218-273X2022-10-011210150710.3390/biom12101507Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3Lukas Gebauer0Muhammad Rafehi1Jürgen Brockmöller2Institute of Clinical Pharmacology, University Medical Center Göttingen, D-37075 Göttingen, GermanyInstitute of Clinical Pharmacology, University Medical Center Göttingen, D-37075 Göttingen, GermanyInstitute of Clinical Pharmacology, University Medical Center Göttingen, D-37075 Göttingen, GermanyStereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported <i>(S)</i>-norepinephrine, SERT preferred the <i>(R)</i>-enantiomer. In contrast, NET and DAT showed higher transport for <i>(R)</i>-epinephrine and SERT for <i>(S)</i>-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most <i>(R)</i>-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their <i>(R)</i>-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters.https://www.mdpi.com/2218-273X/12/10/1507monoamine transportersorganic cation transportersstereoselective drug transportchiral HPLCphenylethylaminesneurotransmitter transport |
| spellingShingle | Lukas Gebauer Muhammad Rafehi Jürgen Brockmöller Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3 Biomolecules monoamine transporters organic cation transporters stereoselective drug transport chiral HPLC phenylethylamines neurotransmitter transport |
| title | Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3 |
| title_full | Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3 |
| title_fullStr | Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3 |
| title_full_unstemmed | Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3 |
| title_short | Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3 |
| title_sort | stereoselectivity in the membrane transport of phenylethylamine derivatives by human monoamine transporters and organic cation transporters 1 2 and 3 |
| topic | monoamine transporters organic cation transporters stereoselective drug transport chiral HPLC phenylethylamines neurotransmitter transport |
| url | https://www.mdpi.com/2218-273X/12/10/1507 |
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