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Enantiomers of stimulants. Part 1. Basics. Amphetamine

Paracelsus

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Let's talk about what enantiomerism is and how it affects substances, pharmacology of the substance and the body.

To begin with, what are isomers. Isomers are chemicals with the same formula, but different structures. A particular atom can attach to a molecule in different places - this is how geometric isomers are obtained. However, we are interested in another group of isomers - optical or stereoisomers. They are differ in that all their atoms are located in the same places of a particular molecule, but at different points in space.

For clarity, let's take a special case of stereoisomers - enantiomers. They will be discussed today and this concept is easy to explain. Enantiomers are mirror stereoisomers. They differ from each other, as a reflection in a mirror differs from the reflected object. The analogy is indicative, but it implies a real object and its "unreal" reflection. While in a pair of enantiomers, both molecules are equally real and at the same time have different biological activity.


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Enantiomers differ from each other in structure as the right palm differs from the left.


It is important to designate a few more terms.

Right and Left. Continuing the analogy with palms, just as there is a right and left palm, there are also right and left enantiomers. They can be absolute R (right) and S (sinister), and relative D(dexter) and L (laevus). There is a difference between these notations, but it will take our conversation into the wilds of chemistry. The main thing we noted is that enantiomers are right and left.

Chirality. A molecule is called chiral or having chirality when it does not combine in space with its mirror image. The term is based on the ancient Greek name of the most recognizable chiral object — the palm. And if I didn't have time to confuse you, then the obvious conclusion is the statement: all enantiomers are chiral.

The chiral center\axis\plane is the part of the molecule from which the mirror difference in space appears. Depending on the complexity and structure of the molecule, it can be an atom (most often carbon), interatomic space, the side of the exit from the plane or the direction of the spiral of the molecule.

Optical activity. The difference between enantiomers is captured even if they are simply stored in a jar. They rotate the plane of polarization of light in different ways. If the rotation occurs clockwise, such an enantiomer is called right-rotating and is denoted by (+). If the plane of polarization rotates counterclockwise, we have a left–rotating enantiomer (-).

Racemate. It is an equivalent mixture of + and - enantiomers. The rotation of one enantiomer is compensated by the rotation of the second. In total, the rotation of the racemic mixture is 0. Such mixtures can be denoted as (±), rac (racem) or RS (SR).


Why does stereoisomerism cause different biological effects of substances?

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Humans are primarily composed of L -amino acids and D-carbohydrates. Protein secondary structure includes right-handed (P-) coiled alpha helices, and most DNA is similarly in a right-handed spiral configuration (termed ‘‘B-DNA,’’ as opposed to left-handed ‘‘Z-DNA’’).

Tertiary structures create unique three-dimensional binding, catalytic, and stabilization domains. On the macroscopic scale, during normal growth and development both the human cardiac and
astrointestinal systems have specific rotational patterns, and additionally, left-right ‘‘mirror’’ symmetry evolves. Unique structural-activity relationships thus proceed from specific architecture constraints at multiple systemic levels. Therefore, in a chiral environment, stereoisomers might experience selective absorption, protein binding, transport, enzyme interactions and metabolism, receptor interactions, and DNA binding.

Thus, each stereoisomer or isomeric mixture can have different pharmacokinetic, pharmacodynamic, therapeutic, and adverse effect profiles. A given structure’s capacity to accommodate chiral disparities will influence the magnitude and type of difference in effects (if any) observed between enantiomers. For example, one enantiomer might be completely unable to complex with a particular receptor or enzyme or lose precise alignment at a catalytic site, whereas at a different molecule, no impairment might occur. These consequences of stereospecificity have been reported for multiple pharmaceutical classes including antibiotic, cardiovascular, chemotherapeutic, pulmonary, rheumatic and psychotropic drugs.


And now it's time (finally) to talk about specific substances.



Amphetamine Enantiomers
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Both stereoisomers of amphetamine are indirect agonists of the catecholaminergic systems, mostly working to prevent the reuptake of dopamine and norepinephrine as well as stimulating their release from nerve terminals. Both the isomers have differing activity. This was shown, for example, in studies aimed at treating narcolepsy with D and L amphetamine individually. D-amphetamine has been shown to be more potent than L-amphetamine both behaviorally and pharmacologically.

The pharmacology of Dextroamphetamine is described in detail here. Let's not dwell on it and shift our attention to Levamphetamine. However, we will need D for comparison. In general, L-amphetamine has more peripheral and cardiovascular side than D, whose activity is mostly central.

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When the in vivo pharmacological profiles of amphetamine’s isomers are compared, D-amphetamine is three to fivefold more potent than L-amphetamine.

Moreover, an analysis of the relative effects of amphetamine’s isomers on individual catecholamines reveals D-amphetamine has greater effects on dopamine than noradrenaline, whereas L-amphetamine has a more balanced action to increase both dopaminergic than noradrenergic neurotransmission.

Dextroamphetamine inhibits the dopamine reuptake almost 10 times more than Levoamphetamine, although the norepinephrine reuptake was the same at normal doses. Low doses of Levoamphetamine cause more effects than Dextroamphetamine on norepinephrine. D-amphetamine also has, albeit little, activity on 5-HT reuptake, where L-amphetamine's activity is so low that it would hardly be worth mentioning.

There is a possibility that because of Levoamphetamine adds to the adrenergic qualities, it leads to sexual enhancement to compare with D-amph. This may explain the reviews that racemate has more effects on sexual function than pure D-amphetamine. On the other hand, for many, any stimulant in any form has an exciting effect.

Also an equal amount of the L-isomer had barely any of the same side-effects as D. It was only when the dosage of Levo-amph was doubled (40mg), that the side-effects were comparable with D-amph (20mg). One old study also shows that Levoamphetamine,
insofar as it has fewer “central side effects” than Dextroamphetamine, may eventually become the drug of choicefor the aggressive,
hostile subgroup of hyperkinetic children/ Yes, there were such studies in the 70s. By the way, since then Levamphetamine appears only in historical reviews.


Half-Life

Its important to note, that half-life of amphetamine highly depends on the isomer. For D-amphetamine, the reported half-life is of approximately 9-11 hours while for L-amphetamine the half-life is reported to be of 11-14 hours. The urine pH can modify this pharmacokinetic parameter which can vary from 7 hours in acid urine to 34 hours for alkaline urine.


Drugs with amphetamine enantiomers
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The numero uno Adderall containing 76% dextroamphetamine to 24% levoamphetamine, when recalculating all salts. In industrial pharmacology, there are other combinations of amphetamine enantiomers. Dextroamphetamine-based drugs are also actively used today. However, Levamphetamine was left out of history. The last representative - L-Amphetamine succinate was sold in Hungary between 1952 and 1955 under the brand name Cydril. It would be interesting to look at the data of this drug, but they are practically not online.

Although Cydril achieved far less attention than either the racemate or D-isomer, clinical trials conducted in the 1970s demonstrated that both isomers of amphetamine were clinically effective in treating ADHD. Today pharmaceutical formulations containing enantiopure levoamphetamine are no longer manufactured. Amphetamine is under international control. The D and L enantiomers as well as the racemate are listed in Schedule II of the United Nations 1971 Convention on Psychotropic Substances.

As for street amphetamine, it is most often a racemate in a ratio close to 1:1, which is most likely due to the optimization of production, It is inefficient to produce pure D-amphetamine. And Levamphetamine is more suitable for the role of a therapeutic drug than a recreational substance. However, history has shown that even in medical pharmacology, Levamphetamine, as a separate substance, had no place.


Thanks for your time.

If you have any experience, information or thoughts about the action and prospects of pure Levamphetamine or in general on the topic, I invite you to a discussion.

In the next part of the series about stereoisomerism, we'll talk about methamphetamine and possibly cocaine.
 

BHBlueberry

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I'm sad when I see such a high-standard articles on this forum - meeting even bigger holes in knowledge and deadly ignorance of people concentrated only on making highest profit..

Thank you for your efforts but you would probably got bigger audience by simply writing something like "L-amph is generally weaker than D-amph, L-amph is bad, m'kay?" Who have time to read all this shit, who really understand what they read? ;)
 

Paracelsus

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Thank you for your assessment. I try to write the kind of material that I would be interested in reading. With the hope that it will be interesting to someone or at least help to go beyond the categories of clip thinking, where everything is simple, dichotomous and understandable. With the same L-amph - I can't say with certainty that its definitely a bad psychoactive agent. In fact, the tasks that it can solve are not selected for it. And, I think, such a view of chemistry, substances, content and communication can eventually help maximize profits.
 

fibinachi

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I for one read through all of it and think its a very important lesson to be learned regarding active substances. The scope of this goes beyond amphetamines.
This is also why methamphetamine of today, in the USA at least, resulting from p2p, is racemic and therefore only half pure. Add in Cut, and were talking about something like 20%-40% purity.
Pure Dextro Methamphetamine, resulting from ephedrine, is quite another beast. This is what dominated in the US in the late 90s-mid 2000s before ephedrine became watched. Its what I grew up on and let me tell you, it might as well be a wholly different drug compared to the racemic mixture. Its still around in small quantities for the discerning buyer. But you try to tell kids today that meth used to be so much better and they think you're crazy.
Levo Methamphetamine is actually a key ingredient in some Vicks vapor rub.
Anecdotally, Ive heard it is responsible for much of the jaw clinching and rise in blood pressure users often report.

Thank you Paracelsus for educating me further on the subject.
 
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