Everyone from school remembers: substances are made up of molecules, molecules are made up of atoms. If the composition is the same, then the substance is the same. However, things are more complicated: of two molecules with the same formula, one may be a necessary medicine and the other a dangerous poison.
Today we will explore why a mirror image of a molecule works differently, why astronauts are prescribed daily amphetamine, how «mirror» versions of ketamine make it an antidepressant or a sleeping pill, and what the «Thalidomide tragedy» is.
Have you ever, looking in the mirror, thought about what would happen if you were real and you from the mirror were combined and compared? It would seem that you would both be the same - two arms, two legs... but reflected horizontally. For example, the mole on the left thigh of your real one would move to the right thigh of your mirror one.
The situation is hypothetical, but it sounds like a description of some kind of bad trip. But in the world of chemistry, the above-described fantasy is commonplace, while having a rather important meaning for the properties of chemical compounds.
Today we will explore why a mirror image of a molecule works differently, why astronauts are prescribed daily amphetamine, how «mirror» versions of ketamine make it an antidepressant or a sleeping pill, and what the «Thalidomide tragedy» is.
Have you ever, looking in the mirror, thought about what would happen if you were real and you from the mirror were combined and compared? It would seem that you would both be the same - two arms, two legs... but reflected horizontally. For example, the mole on the left thigh of your real one would move to the right thigh of your mirror one.
The situation is hypothetical, but it sounds like a description of some kind of bad trip. But in the world of chemistry, the above-described fantasy is commonplace, while having a rather important meaning for the properties of chemical compounds.
What are «mirror» substances?
«Mirror» substances are called optical isomers. The term, by the way, is not the most successful, as it describes only the rotation of the polarization of light when it passes through solutions of different optical isomers of the same substance. A more widely used term is enantiomers. This concept is best illustrated by a picture.
In chemistry, a compound takes only one configuration, the energetically advantageous one, which is caused by the interaction of the electron shells of the atoms. In this case the trihedral pyramid (tetrahedron) is such an advantageous configuration of mutual arrangement of atoms connected with the central carbon atom. And the arrangement of its «corners» can be either like on the left hand or like on the right hand, and these «reflections» cannot be combined, no matter how you twist them.
By the way, chemists don't think much about it and call optical isomers that way - left-rotating (L-isomers) and right-rotating (D-isomers).
It may seem like another muddle of physics or chemistry and their three-story equations, but not at all: by some miracle (actually thermodynamics) it turns out that we are all composed of amino acids with an L-conformation and carbohydrates with a D-conformation!
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«Mirror» substances are called optical isomers. The term, by the way, is not the most successful, as it describes only the rotation of the polarization of light when it passes through solutions of different optical isomers of the same substance. A more widely used term is enantiomers. This concept is best illustrated by a picture.
In chemistry, a compound takes only one configuration, the energetically advantageous one, which is caused by the interaction of the electron shells of the atoms. In this case the trihedral pyramid (tetrahedron) is such an advantageous configuration of mutual arrangement of atoms connected with the central carbon atom. And the arrangement of its «corners» can be either like on the left hand or like on the right hand, and these «reflections» cannot be combined, no matter how you twist them.
By the way, chemists don't think much about it and call optical isomers that way - left-rotating (L-isomers) and right-rotating (D-isomers).
It may seem like another muddle of physics or chemistry and their three-story equations, but not at all: by some miracle (actually thermodynamics) it turns out that we are all composed of amino acids with an L-conformation and carbohydrates with a D-conformation!
Of course, there are exceptions to this rule: D-amino acids are found in nature, but they are few, they have very specific properties (e.g., metabolic regulation in some bacteria), and they are not included in proteins.
In Miller's famous experiment, which reproduced the conditions of the ancient Earth and the so-called abiogenesis stage - the formation of organic compounds from inorganics, the output was an equal mixture of L- and D-amino acids.
There are several hypotheses explaining the predominance of L-forms (for example, that the radiation of the «young» Sun was partially polarized and absorbed by D-amino acids with their subsequent destruction), but at the moment they have made little progress in explaining why the early protoorganisms still «chose» L-amino acids for self-reproduction.
However, all scientists agree on one thing: the phenomenon of «homochirality», that is, the use of exclusively L- or D-amino acids, is one of the key points in the stability of protein molecules.
Interestingly, our bodies are unable to digest D-amino acids and L-carbohydrates. This nice fact led biochemical scientists to a very sadistic mental experiment known as the «mirror world».
Imagine that you find yourself on a planet identical to Earth, but where the chirality of amino acids and carbohydrates is reversed. You would die of starvation (and possibly poisoning) even with an abundance of easily digestible food.
In Miller's famous experiment, which reproduced the conditions of the ancient Earth and the so-called abiogenesis stage - the formation of organic compounds from inorganics, the output was an equal mixture of L- and D-amino acids.
There are several hypotheses explaining the predominance of L-forms (for example, that the radiation of the «young» Sun was partially polarized and absorbed by D-amino acids with their subsequent destruction), but at the moment they have made little progress in explaining why the early protoorganisms still «chose» L-amino acids for self-reproduction.
However, all scientists agree on one thing: the phenomenon of «homochirality», that is, the use of exclusively L- or D-amino acids, is one of the key points in the stability of protein molecules.
Interestingly, our bodies are unable to digest D-amino acids and L-carbohydrates. This nice fact led biochemical scientists to a very sadistic mental experiment known as the «mirror world».
Imagine that you find yourself on a planet identical to Earth, but where the chirality of amino acids and carbohydrates is reversed. You would die of starvation (and possibly poisoning) even with an abundance of easily digestible food.
Amphetamine Brothers
Let's get a little bit above the depths of biochemistry and look at how chirality affects our daily lives. For example, let's take such a well-known drug as amphetamine. It is approved by the FDA (Food and Drugs Administration) and sold under the brand name Adderall for the treatment of narcolepsy.
It has two enantiomers, L-amphetamine (levoamphetamine) and D-amphetamine (dextroamphetamine, or dexedrine).
With classical synthesis techniques, the output is a so-called racemate, a mixture of L- and D-enantiomers in approximately equal proportions. There are also methods of «stereoselective» synthesis that allow one of the enantiomers to be obtained selectively.
As for the biological properties of levoamphetamine and dexedrine, the differences are quite significant - levoamphetamine has difficulty crossing the BBB (blood-brain barrier, a system of specialized cells and proteins that «filter» chemical substances entering brain tissue) and has mainly peripheral effects - increased blood pressure, increased heart rate.
While the D-enantiomer has mainly CNS effects: it is more than four times more effective in dopamine release than the L-isomer.
Let's get a little bit above the depths of biochemistry and look at how chirality affects our daily lives. For example, let's take such a well-known drug as amphetamine. It is approved by the FDA (Food and Drugs Administration) and sold under the brand name Adderall for the treatment of narcolepsy.
It has two enantiomers, L-amphetamine (levoamphetamine) and D-amphetamine (dextroamphetamine, or dexedrine).
With classical synthesis techniques, the output is a so-called racemate, a mixture of L- and D-enantiomers in approximately equal proportions. There are also methods of «stereoselective» synthesis that allow one of the enantiomers to be obtained selectively.
As for the biological properties of levoamphetamine and dexedrine, the differences are quite significant - levoamphetamine has difficulty crossing the BBB (blood-brain barrier, a system of specialized cells and proteins that «filter» chemical substances entering brain tissue) and has mainly peripheral effects - increased blood pressure, increased heart rate.
While the D-enantiomer has mainly CNS effects: it is more than four times more effective in dopamine release than the L-isomer.
So why does this happen? One of the basic rules of biochemistry is that a substrate must fit an enzyme like a key to a lock. The same rule is also true for pharmacology: a drug substance must have structural affinity to its target.
Since the «binding site» of the target protein does not recognize the structure of the whole molecule, but only the arrangement of individual atoms, and on this basis the protein molecule either stops its work or is activated, a small difference in the spatial position of one or two atoms can play a huge role.
If you look closely at the bulk structure of different amphetamine enantiomers, you will see the difference in the position of atoms in space (blue is the nitrogen atom). And this is a key point in binding to proteins, for example to the same dopamine transporter (DAT).
Since the «binding site» of the target protein does not recognize the structure of the whole molecule, but only the arrangement of individual atoms, and on this basis the protein molecule either stops its work or is activated, a small difference in the spatial position of one or two atoms can play a huge role.
If you look closely at the bulk structure of different amphetamine enantiomers, you will see the difference in the position of atoms in space (blue is the nitrogen atom). And this is a key point in binding to proteins, for example to the same dopamine transporter (DAT).
Fun fact: Dexedrine was used in space medicine and on American astronaut flights. You see, playing with pressure and hemodynamics in zero gravity, with active redistribution of body fluids, is quite dangerous. But we need something to keep the astronauts toned up, don't we?
Here is the composition of the astronaut's first aid kit - as you can see in the «Stowed/Used» columns, the moon explorers liked to mix dexedrine with scopolamine.
This mixture was reported to be extremely effective in treating nausea. There was also a regulation requiring astronauts to take 10 mg of Dexedrine as they descended from orbit.
Here is the composition of the astronaut's first aid kit - as you can see in the «Stowed/Used» columns, the moon explorers liked to mix dexedrine with scopolamine.
This mixture was reported to be extremely effective in treating nausea. There was also a regulation requiring astronauts to take 10 mg of Dexedrine as they descended from orbit.
A safe tranquilizer with nuance
In the history and pharmacology of the use of various enantiomers, in addition to the fun conquest of the moon by amphetamine, there have also been some very dark pages, such as thalidomide.
Women are known to become «conditionally sane» during pregnancy due to a major «hormonal storm» that manifests itself as insomnia, nausea, restlessness, and strange taste preferences like demanding a jam and ham sandwich at 1 a.m. In the late 1950s, doctors turned their attention to the increasingly popular thalidomide, a safe tranquilizer without serious side effects.
Yes, it did relieve anxiety and strange behavioral abnormalities, but here's the kicker - it had never been used in pregnancy before, not even in rats.
Just 2-3 years after its introduction into practice, doctors were surprised by the birth of a huge number of children with all kinds of deformities: some had no legs, some had no arms, and some were born without a brain at all (literally). They began to look up the histories of prescription drugs in pregnancy and found thalidomide.
In the history and pharmacology of the use of various enantiomers, in addition to the fun conquest of the moon by amphetamine, there have also been some very dark pages, such as thalidomide.
Women are known to become «conditionally sane» during pregnancy due to a major «hormonal storm» that manifests itself as insomnia, nausea, restlessness, and strange taste preferences like demanding a jam and ham sandwich at 1 a.m. In the late 1950s, doctors turned their attention to the increasingly popular thalidomide, a safe tranquilizer without serious side effects.
Yes, it did relieve anxiety and strange behavioral abnormalities, but here's the kicker - it had never been used in pregnancy before, not even in rats.
Just 2-3 years after its introduction into practice, doctors were surprised by the birth of a huge number of children with all kinds of deformities: some had no legs, some had no arms, and some were born without a brain at all (literally). They began to look up the histories of prescription drugs in pregnancy and found thalidomide.
Naturally, its use was immediately halted and a multi-year investigation began as to how it was allowed on the market at all. I will not bore the reader with the vicissitudes of the trials, but I will get to the point.
The synthesis, which was not stereoselective, produced two enantiomers, D- and L-. One of them was a really good and suitable tranquilizer without side effects, the other was a teratogen, i.e. causing congenital deformities.
The essence of the toxic action of thalidomide (the evil brother of the enantiomer) was that it, like mustard gas, was incorporated into the DNA. Although this is only one of the many mechanisms of toxic action that have been discovered, in a situation where you have a mass of constantly dividing cells that is growing by leaps and bounds, this is what is critical.
The synthesis, which was not stereoselective, produced two enantiomers, D- and L-. One of them was a really good and suitable tranquilizer without side effects, the other was a teratogen, i.e. causing congenital deformities.
The essence of the toxic action of thalidomide (the evil brother of the enantiomer) was that it, like mustard gas, was incorporated into the DNA. Although this is only one of the many mechanisms of toxic action that have been discovered, in a situation where you have a mass of constantly dividing cells that is growing by leaps and bounds, this is what is critical.
The series of tragic events and disabilities caused by this drug has been called the thalidomide tragedy. The most interesting thing is that the manufacturing company did not go bankrupt at all on the payments to the victims; moreover, Grünenthal is still doing fine and thriving, producing the opioid analgesic tramadol.
And sometimes it also siphons off a measly 50 million euros to various organizations of people with disabilities.
Also, of course, our «beloved» FDA has introduced several additional mandatory teratogenicity tests, which, before the thalidomide tragedy, were the sole responsibility of the pharmaceutical companies.
Ketamine: hallucinogen, antidepressant, or sedative?
In addition to this, there are many other cases in which the location of one or two atoms in a molecule was critical, such as in the synthesis of citalopram and escitalopram (L-isomer).
The second differs from the first in its greater affinity (selectivity) for the serotonin transporter, which pumps serotonin back into the neuron after release. When the transporter is blocked, the time that serotonin stays in the intersynaptic space increases, and the antidepressant effects of the drug increase accordingly.
Of other promising antidepressants, we can mention ketamine, which had previously been used exclusively for general anesthesia. It also exists as two optical isomers - arketamine (R-ketamine) and esketamine (S-ketamine).
For a long time, physicians and pharmacologists did not pay attention to the differences between the racemate and mono-use individual forms, but now that the substance is being actively studied as an antidepressant and for the treatment of various kinds of anxiety disorders, these differences have received more attention.
Arketamine is more than 4 times less active than esketamine with respect to NMDA-receptors, whose blockade is the cause of the fairy hallucinations.
And sometimes it also siphons off a measly 50 million euros to various organizations of people with disabilities.
Also, of course, our «beloved» FDA has introduced several additional mandatory teratogenicity tests, which, before the thalidomide tragedy, were the sole responsibility of the pharmaceutical companies.
Ketamine: hallucinogen, antidepressant, or sedative?
In addition to this, there are many other cases in which the location of one or two atoms in a molecule was critical, such as in the synthesis of citalopram and escitalopram (L-isomer).
The second differs from the first in its greater affinity (selectivity) for the serotonin transporter, which pumps serotonin back into the neuron after release. When the transporter is blocked, the time that serotonin stays in the intersynaptic space increases, and the antidepressant effects of the drug increase accordingly.
Of other promising antidepressants, we can mention ketamine, which had previously been used exclusively for general anesthesia. It also exists as two optical isomers - arketamine (R-ketamine) and esketamine (S-ketamine).
For a long time, physicians and pharmacologists did not pay attention to the differences between the racemate and mono-use individual forms, but now that the substance is being actively studied as an antidepressant and for the treatment of various kinds of anxiety disorders, these differences have received more attention.
Arketamine is more than 4 times less active than esketamine with respect to NMDA-receptors, whose blockade is the cause of the fairy hallucinations.
In its turn, the R-isomer has two unique properties: activation of AMPA-receptors (receptors normally activated by glutamate and involved in the formation of the so-called long-term potentiality - one of the biological bases of memory process) and formation of a unique metabolite characteristic only for arketamine - (2R,6R)-HNK.
This metabolite, simply called hydroxynoroquethamine, or more precisely, its R-stereoisomer, is a moderately strong psychostimulant and a good antidepressant.
This metabolite, simply called hydroxynoroquethamine, or more precisely, its R-stereoisomer, is a moderately strong psychostimulant and a good antidepressant.
Its twin brother, esketamine, is also worth mentioning. It is a more potent NMDA-antagonist and dopamine reuptake inhibitor. However, if you think this is a good thing, you would be wrong. When there is a lot of this neurotransmitter, one begins to feel, to put it mildly, out of touch with this reality.
An example of such a condition would be alcoholic delirium - in its mechanism, this pathological state partially resembles the effects of pure esketamine administration.
However, if the patient is injected very much esketamine, he will fall into a very mild (in terms of tolerance) anesthesia, after leaving which the person will be almost completely free of postnarcotic agitation, which is quite often observed when using «classic» racemic ketamine.
An example of such a condition would be alcoholic delirium - in its mechanism, this pathological state partially resembles the effects of pure esketamine administration.
However, if the patient is injected very much esketamine, he will fall into a very mild (in terms of tolerance) anesthesia, after leaving which the person will be almost completely free of postnarcotic agitation, which is quite often observed when using «classic» racemic ketamine.
And this is just a small fraction of all the possible examples of differences in the biological activity of optical isomers of drugs.
Many clinical trials are currently underway that should reveal these most clinically significant differences in activity in substances that have previously been used only as racemic mixtures.
And these differences can be negligible in their strength (nothing dangerous will happen to the patient if he uses citalopram instead of escitalopram) or very important, as in the case of thalidomide.
Many clinical trials are currently underway that should reveal these most clinically significant differences in activity in substances that have previously been used only as racemic mixtures.
And these differences can be negligible in their strength (nothing dangerous will happen to the patient if he uses citalopram instead of escitalopram) or very important, as in the case of thalidomide.