Enantiomer of amphetamine

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 An older approved ADHD drug, pemoline (Cylert ), was withdrawn from the market in 2005 due to reported... 

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. 

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

Usually the objective in forming diastereomers is to use a chiral reagent that is 100% of one isomer and to use an achiral chromatographic system. As an example, Clark and Barksdale33 separated the R and S enantiomers of amphetamine after reacting the racemic mixture with l[(4-nitro-... 

A number of recent studies extend the observation of stereoselectivity of drug metabolism. The inactive d-isomer of propanolol was metabolized in rats with a two-fold shorter plasma half-life than l-propanolol . The anti-inflammatory agent l-a-methylfluorene-2-acetic acid was isomerized in dogs to the d-enantiomer , thus being another example of stereospecific metabolic inversion. Whereas the individual R and S enantiomers of 15 were metabolized at similar rates, the half-life of the more active R isomer was prolonged in the racemic mixture, perhaps due to inhibition of metabolism of the R isomer by the S isomer. A similar effect was observed with the R and S enantiomers of amphetamines , which further illustrates that racemates may exhibit a biological profile different from that anticipated on the basis of the activity of the component enantiomers. 

Amphetamines and Phenethylamines. Deficiency in the p-hydroxylation of amphetamine was one of the observations that led to the discovery of the CYP2D6 polymorphism (Bring et al. 1970 Smith 1986). A single oral administration of the radiolabelled enantiomers of amphetamine to three volunteers with subsequent analysis of urine indicated that about 5 percent of (+)-amphetamine was converted to p-hydroxyamphetamine in two subjects but to a much less extent in the third subject, who was later found to have CYP2D6 deficiency (Smith 1986). The main excretion product was unchanged amphetamine (although the extent of excretion is known to be pH dependent), and the major metabolites were products of side... 

A Ramseier, J Caslavaska, W Thormann. Stereoselective screening for and confirmation of urinary enantiomers of amphetamine, methamphetamine, designer drugs, metadone and selected metabolites by capillary electrophoresis. Electrophoresis 20 2726-2738, 1999. 

The association constants for CyD complexes with chiral guests are generally different and mostly quantitatively determined by the chemical shift titration experiments. However, as mentioned above, other NMR parameters, such as relaxation rates [10, 70] or self-diffusion coefficients, may also be used. Both those parameters were successfully applied for the enantiodifferentiation and determination of association constants in complexes of the trifluoroacetate salts of the enantiomers of amphetamine, ephedrine, and propranolol with 2,6-di-O-dodecyl-a-CyD and its p analogue [71]. The DOSY technique was employed for the determination of diffusion coefficients of enantiomers of cyclohexanone derivatives complexed with a-, j8-and y-CyDs as well as with their per-O-methylated analogues [72]. 

The Separation of the Enantiomers of Amphetamine, Methamphetamine and Ephedrine Courtesy of ASTEC Inc. 

Amphetamine is a prescription stimulant used in the treatment of ADHD (attention-deficit hyperactivity disorder) and chronic fatigue syndrome. During World War II it was used heavily by soldiers to reduce fatigue and increase alertness. Draw the enantiomer of amphetamine. 

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. 

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. 

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 ... 

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. 

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