Amphetamine enantiomers

Cody JT, Schwarzhoff R. Interpretation of methamphetamine and amphetamine enantiomer data. J Anal Toxicol 1993 17 321-6. 

Liu JH, Tsay JT. Use of chiral lanthanide shift reagents for the nuclear magnetic resonance spectrometric determination of amphetamine enantiomers. Analyst 1982 107 544—549. 

On the other hand, because enantiomers differ in their three-dimensional structure, they often interact with biochemical molecules in different ways. As a result, they may show quite different physiological properties. Consider, for example, amphetamine, often used illicitly as an upper or pep pill. Amphetamine consists of two enantiomers ... 

In earlier proposals (Anderson et al. 1978), based on this stereoselectivity for the S enantiomer of MDMA, it was suggested that, rather than having a direct effect at serotonin receptors, perhaps MDMA was a neurotransmitterreleasing agent, acting in a fashion similar to amphetamine, for which the S enantiomer is also more active than the R enantiomer. A subsequent study... 

These data clearly illustrate the enantioselectivity of the (-l-)-isomers of MDA, MDMA, and MBDB in producing an MDMA-like stimulus and underscore the fact that in vitro studies of the biochemical pharmacology of these substances should reveal similar selectivity, once the primary pharmacological process underlying the interoceptive cue is identified. The data also indicate that (-l-)-MDA is the most potent of all the drugs tested in MDMA- or in (-t)-MBDB-trained animals. The faet that (-l-)-MDA does not substitute in amphetamine-trained animals in our studies supports the argument that the pharmacology of this enantiomer of MDA is MDMA-like and is not like amphetamine. 

Another study underway has begun to examine the effect of paramethoxy-amphetamine (PMA) in MDMA-trained rats. After testing a few doses, it appears that full substitution may occur and that the S enantiomer of PMA... 

D-amphetamine The more potent of the two enantiomers of the psychostimulant amphetamine. 

This view offers an explanation for the stereoselectivity of the phenylisopro-pylamines, i.e., the isomer that is more active is the one that presents least interference to the drug-receptor interaction. This idea would be consistent with the observation that the R enantiomers of the phenylisopropylamines have receptor affinity similar to their nonalpha-methylated homologs, and that the alpha-methyl of the S enantiomer of the amphetamines has a deleterious effect on affinity (72,78). There is no strongly compelling evidence in favor of either of the above hypotheses, however, and either is tenable. 

Many stimulants, such as amphetamine, methamphetamine, and caffeine contain nitrogen atoms, which makes NPD analysis fairly straightforward (eg. Koide et al., 1998 Bach et al., 1999). Enantiomeric separation can be of particular importance for these drugs. A review by Liu and Liu (2002) provides extensive examples of methods for the determination of amphetamine and methamphetamine enantiomers and includes examples... 

Van Boadaer JF, Lambert WE, Theinpont L, De Leenheer AP 1997. Quantitative determination of amphetamine and a-phenylethylamine enantiomers in judicial samples using capillary gas chromatography. J Anal Toxicol 21 5. 

Analysis using a CMPA is usually resolved on a nonchiral column. A transient diastereomeric complex is formed between the enantiomer and the chiral component in the mobile phase, similar to the complexes formed with chiral stationary phases. A review by Liu and Liu (2002) cites several papers where addition of CPMAs has been used in analyzing amphetamine-related compounds. Some CPMAs include amino acid enantiomers, metal ions, proteins, and cyclodextrins. Advantages of this method of analysis include the use of less expensive columns and more flexibility in the optimization of chiral separation (Misl anova and Hutta, 2003). 

Peters FT, Kraemer T, Maurer HH. 2002. Drug testing in blood validated negative-ion chemical ionization gas chromatographic-mass spectrometric assay for determination of amphetamine and methamphetamine enantiomers and its application to toxicology cases. Clin Chem 48 1472. 

When using PFT with a neutral selector, it is quite difficult to avoid any entrance of the chiral selector into the ionization source, particularly at a high pH, where EOF is important. The use of BGE at low pH and/or coated capillary to minimize EOF is therefore mandatory. However, the coaxial sheath gas, which generally assists the ionization process, leads to an aspirating phenomenon of the chiral selector in the MS direction. Javerfalk et al. were the first to apply PFT with a neutral methyl-/i-CD for the separation of racemic bupivacaine and ropivacaine with a polyacrylamide-coated capillary and an acidic pH buffer (pH 3). Cherkaoui et al. employed another neutral CD (HP-/1-CD) with a PVA-coated capillary for the analysis of amphetamines and their derivatives. To prevent a detrimental aspiration effect, analyses were carried out without nebulization pressure. Numerous other studies presented excellent results such as the enantioselective separation of adrenoreceptor antagonist drugs using tandem mass spectrometry (MS/MS) the separation of clenbuterol enantiomers after solid-phase extraction (SPE) of plasma samples or the use of CD dual system for the simultaneous chiral determination of amphetamine, methamphetamine, dimethamphetamine, and p-hydroxymethamphetamine in urine. 

As of 2006, there are several branded medications approved for the treatment of ADHD however, there are only three chemicals that make up the primary active ingredients in these drugs the (5)-enantiomer of amphetamine (1), the 2(/ ),2 (7 )-enantiomer of methylphenidate (2), and the (/ )-enantiomer of atomoxetine (3). An older approved ADHD drug, pemoline (Cylert ), was withdrawn from the market in 2005 due to reported... 

All three ADHD-approved chemical entities have at least one chiral center, a feature that has led to a number of interesting syntheses of these compounds over the years. Amphetamine (1) and methylphenidate (2) were discovered before the modern era of asymmetric and enantioselective synthesis, and are sold as racemic, single-enantiomer, and enantio-enriched formulations. Atomoxetine (3), hrst presented in a 1977 Eli Lilly patent, was developed as a single-enantiomer drug (Molloy and Schmiegel, 1977). 

Amphetamine (1) is a very simple phenethylamine, described in the chemical literature as early as 1887 (Edeleano, 1887). Smith, Kline and French (now GSK) filed a patent on the synthesis and use of amphetamine in 1930 (Nabenhauer, 1930), and the enantiomers were assigned in 1932 (Leithe, 1932 V-Braun and Friehmelt, 1933). Not surprisingly, early access to chiral material relied on classical crystallization-based resolutions (Gillingham, 1962 Nabenhaur, 1942). The early, racemic syntheses of amphetamine fall into four major classifications according to the method used to make the C-N bond ... 

Another HMG-CoA reductase inhibitor, benfluorex (structurally an amphetamine), and its D enantiomer, dexfenfluramine, have been withdrawn after several serious pulmonary arterial hypertension cases (Figure 8.59). 

Amphetamine and methamphetamine occur as structural isomers and stereoisomers. Structural isomers are compounds with the same empirical formula but a different atomic arrangement, e.g., methamphetamine and phentermine. Stereoisomers differ in the three-dimensional arrangement of the atoms attached to at least one asymmetric carbon and are nonsuperimposable mirror images. Therefore, amphetamine and methamphetamine occur as both d- and L-isomeric forms. The two isomers together form a racemic mixture. The D-amphetamine form has significant stimulant activity, and possesses approximately three to four times the central activity of the L-form. It is also important to note that the d- and L-enantiomers may have not only different pharmacological activity but also varying pharmacokinetic characteristics. 

FIGURE 12-4. The enantiomer of -amphetamine is /-amphetamine, which has no preference between the norepinephrine and the dopamine transporters. Thus, it will target both the norepinephrine reuptake site (shown here), as well as the dopamine reuptake site (shown in Fig. 12-2). -Amphetamine is selective for the dopamine transporter. 

One of the most commonly used class of derivatization agents for diasteromer formation are isothiocyanates and isocyanates. Enantiomers of /3-blockers, amphetamine, epinephrine, methamphetamine, and mexiletine have been resolved after derivatization with these agents. Isothiocyanates produce thiourea derivatives upon reaction with primary and secondary amines. Thiourea derivatives also provide a strong UV absorbance for the detection of enantiomers lacking a strong UV chromophore. Isocyanates produce ureas when reacted with amines. The physical properties of these ureas are similar to thiourea derivatives. Isocyanates will also react with alcohols to yield carbamates. 

R. W. Souter, Gas chromatographic resolution of enantiomeric amphetamine and related amines. II. Effect of cyclic structures on diastereomer and enantiomer resolution, J. Chromatogr., 114 301 (1975). 

J. Pfordt, Separation of enantiomers of amphetamine and related amines by HPLC, FreseniusZ. Anal. Chem., 325 625 (1986). 

E. D. Lee, J. D. Henion, C. A. Brunner, I. W. Wainer, T. D. Doyle, and J. Gal, High-performance liquid chromatographic chiral stationary phase separation with filament on thermospray mass spec-trometric identification of the enantiomer contaminant (S)-( + )meth-amphetamine, Anal. Chem., 55 1349 (1986). 

I. S. Lurie, Micellar electrokinetic capillary chromatography of the enantiomers of amphetamine, methamphetamine and their hy-droxyphene-thylamine percursors, J. Chromatogr., 605 269 (1992). 

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