Separation of 1,3-Dimethylamylamine (1,3-DMAA) Stereoisomers, a Stimulant Drug, by Liquid Chromatography
Background: 1,3-Dimethylamylamine (1,3-DMAA), also known as methylhexanamine, is a central nervous system stimulant with structural similarities with amphetamines and, therefore, presenting overlapping biological and detrimental effects [1]. Despite being banned, the presence of 1,3-DMAA in doping...
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Rede Académica das Ciências da Saúde da Lusofonia - RACS
2025-06-01
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| author | Maria de Almeida Mexia de Almeida Virgínia M. Gonçalves Alexandra S. Maia Diana Dias da Silva Ricardo Jorge Dinis-Oliveira Cláudia Ribeiro |
| author_facet | Maria de Almeida Mexia de Almeida Virgínia M. Gonçalves Alexandra S. Maia Diana Dias da Silva Ricardo Jorge Dinis-Oliveira Cláudia Ribeiro |
| author_sort | Maria de Almeida Mexia de Almeida |
| collection | DOAJ |
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Background: 1,3-Dimethylamylamine (1,3-DMAA), also known as methylhexanamine, is a central nervous system stimulant with structural similarities with amphetamines and, therefore, presenting overlapping biological and detrimental effects [1]. Despite being banned, the presence of 1,3-DMAA in doping controls and dietary supplements continues to be of significant concern. This molecule has two stereogenic centres and, thus, four stereoisomers [2]. It is widely recognized that enantiomers may exhibit different biological activities, including pharmacokinetics, pharmacodynamics, and toxicity. Consequently, developing analytical methods for enantioselective separation of 1,3-DMAA is crucial to isolate and accurately determine the risks associated with each of these stereoisomers.
Objective: To develop a semipreparative liquid chromatography with diode array detection (LC-DAD) method for separating the stereoisomers of 1,3-DMAA.
Methods: For that, 1,3-DMAA was derivatized using the enantiomeric pure reagent (R)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride ((R)-MTPA-Cl) for the formation of diastereomers. Subsequently, the solution was evaporated, reconstituted in acetonitrile or mobile phase (under testing) or 0.1% formic acid, and analyzed by LC-DAD. Different conventional and chiral analytical columns and chromatographic conditions were tested depending on the column used. Seventy-two tests were carried out with 6 different columns and under different conditions.
Results: Preliminary results showed that the derivatization procedure allowed the formation of four 1,3-DMAA diastereomers confirmed by gas chromatography. In liquid chromatography tests, the running conditions were optimized, and the best conditions allowed the separation of two pairs of diastereomers. For the Luna 3µm PFP column, the best eluents were ultrapure water and methanol, both with 0.1% formic acid, with a gradient elution; for the Lux® 3µm Amylose-1 column the best eluents were hexane and isopropanol, both with 0.1% diethylamine by isocratic elution; for the RP-18 LiChrospher® column, the best eluents were ultrapure water, methanol and acetonitrile, all with 0.1% formic acid, by gradient elution.
Conclusions: Chromatographic conditions for enantioselective separation of the two stereoisomers of 1,3-DMAA by LC-DAD have been optimized. The isolation of each stereoisomer is crucial for assessing the differential pharmacokinetics and pharmacodynamics and, consequently, to unveil the perils associated with their presence in food supplement and biological samples.
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| publishDate | 2025-06-01 |
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| spelling | doaj-art-e02c4d826cf74637892b9ea3ec3efb752025-08-20T03:17:51ZengRede Académica das Ciências da Saúde da Lusofonia - RACSRevSALUS2184-48602184-836X2025-06-017Sup10.51126/revsalus.v7isup.1030Separation of 1,3-Dimethylamylamine (1,3-DMAA) Stereoisomers, a Stimulant Drug, by Liquid ChromatographyMaria de Almeida Mexia de Almeida0Virgínia M. Gonçalves1Alexandra S. Maia2Diana Dias da Silva3Ricardo Jorge Dinis-Oliveira4Cláudia Ribeiro5Associate Laboratory i4HB – Institute for Health and Bioeconomy, University Institute of Health Sciences. UCIBIO – Applied Molecu-lar Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences.Associate Laboratory i4HB – Institute for Health and Bioeconomy, University Institute of Health Sciences. UCIBIO – Applied Molecu-lar Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences. UNIPRO – Oral Pathology and Rehabilitation Research UnitAssociate Laboratory i4HB – Institute for Health and Bioeconomy, University Institute of Health Sciences. UCIBIO – Applied Molecu-lar Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health SciencesREQUIMTE/LAQV, ESS, Polytechnic of Porto. UCIBIO – Applied Molecular Biosciences Unit, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto. Associate Laboratory i4HB ‒ Institute for Health and Bioeconomy, University of Porto. UCIBIO. Asso-ciate Laboratory i4HBAssociate Laboratory i4HB – Institute for Health and Bioeconomy, University Institute of Health Sciences. UCIBIO – Applied Molecu-lar Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health SciencesAssociate Laboratory i4HB – Institute for Health and Bioeconomy, University Institute of Health Sciences. UCIBIO – Applied Molecu-lar Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences Background: 1,3-Dimethylamylamine (1,3-DMAA), also known as methylhexanamine, is a central nervous system stimulant with structural similarities with amphetamines and, therefore, presenting overlapping biological and detrimental effects [1]. Despite being banned, the presence of 1,3-DMAA in doping controls and dietary supplements continues to be of significant concern. This molecule has two stereogenic centres and, thus, four stereoisomers [2]. It is widely recognized that enantiomers may exhibit different biological activities, including pharmacokinetics, pharmacodynamics, and toxicity. Consequently, developing analytical methods for enantioselective separation of 1,3-DMAA is crucial to isolate and accurately determine the risks associated with each of these stereoisomers. Objective: To develop a semipreparative liquid chromatography with diode array detection (LC-DAD) method for separating the stereoisomers of 1,3-DMAA. Methods: For that, 1,3-DMAA was derivatized using the enantiomeric pure reagent (R)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride ((R)-MTPA-Cl) for the formation of diastereomers. Subsequently, the solution was evaporated, reconstituted in acetonitrile or mobile phase (under testing) or 0.1% formic acid, and analyzed by LC-DAD. Different conventional and chiral analytical columns and chromatographic conditions were tested depending on the column used. Seventy-two tests were carried out with 6 different columns and under different conditions. Results: Preliminary results showed that the derivatization procedure allowed the formation of four 1,3-DMAA diastereomers confirmed by gas chromatography. In liquid chromatography tests, the running conditions were optimized, and the best conditions allowed the separation of two pairs of diastereomers. For the Luna 3µm PFP column, the best eluents were ultrapure water and methanol, both with 0.1% formic acid, with a gradient elution; for the Lux® 3µm Amylose-1 column the best eluents were hexane and isopropanol, both with 0.1% diethylamine by isocratic elution; for the RP-18 LiChrospher® column, the best eluents were ultrapure water, methanol and acetonitrile, all with 0.1% formic acid, by gradient elution. Conclusions: Chromatographic conditions for enantioselective separation of the two stereoisomers of 1,3-DMAA by LC-DAD have been optimized. The isolation of each stereoisomer is crucial for assessing the differential pharmacokinetics and pharmacodynamics and, consequently, to unveil the perils associated with their presence in food supplement and biological samples. https://revsalus.com/index.php/RevSALUS/article/view/1030enantioselectivity; dietary supplements; chromatographic analysis |
| spellingShingle | Maria de Almeida Mexia de Almeida Virgínia M. Gonçalves Alexandra S. Maia Diana Dias da Silva Ricardo Jorge Dinis-Oliveira Cláudia Ribeiro Separation of 1,3-Dimethylamylamine (1,3-DMAA) Stereoisomers, a Stimulant Drug, by Liquid Chromatography RevSALUS enantioselectivity; dietary supplements; chromatographic analysis |
| title | Separation of 1,3-Dimethylamylamine (1,3-DMAA) Stereoisomers, a Stimulant Drug, by Liquid Chromatography |
| title_full | Separation of 1,3-Dimethylamylamine (1,3-DMAA) Stereoisomers, a Stimulant Drug, by Liquid Chromatography |
| title_fullStr | Separation of 1,3-Dimethylamylamine (1,3-DMAA) Stereoisomers, a Stimulant Drug, by Liquid Chromatography |
| title_full_unstemmed | Separation of 1,3-Dimethylamylamine (1,3-DMAA) Stereoisomers, a Stimulant Drug, by Liquid Chromatography |
| title_short | Separation of 1,3-Dimethylamylamine (1,3-DMAA) Stereoisomers, a Stimulant Drug, by Liquid Chromatography |
| title_sort | separation of 1 3 dimethylamylamine 1 3 dmaa stereoisomers a stimulant drug by liquid chromatography |
| topic | enantioselectivity; dietary supplements; chromatographic analysis |
| url | https://revsalus.com/index.php/RevSALUS/article/view/1030 |
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