When first released in the 1950s, pharmaceutical drug thalidomide was promoted for a number of issues, including anxiety, trouble sleeping, and morning sickness. The over-the-counter medicine was initially declared “completely safe, even during pregnancy,” as its developers “could not find a dose high enough to kill a rat”. Tragically, thalidomide was found to have serious side-effects - issues such as birth defects arose in large numbers when pregnant women took the drug. The drug was quickly removed from the market in 1961, but an estimated 10,000 mothers who had already taken it experienced extreme issues in their pregnancy, and about 40% of children born died around the time of birth. Those who survived had limb, eye, urinary tract, and heart problems. This was labelled the 'Thalidomide Disaster' of the late 50s, and was a key case study used to promote stronger drug testing and regulations in the pharmaceutical industry.

The story of the Thalidomide disaster is heartbreaking, but it illustrates why a drug's stereochemistry is so crucial to investigate in pharmacology.

An obvious question which arises in relation to this disaster is how the drug could have possibly passed clinical trials when it was clearly unsafe for use in a large demographic of the population. Alongside the central factor of insufficient testing, there lies another, more intricate reason for the drug's adverse effects.

Twenty years after the disaster, Blaschke et al. reported that one of the two enantiomers of thalidomide was in fact teratogenic (causing birth defects). An enantiomer of a molecule is its optical isomer of a molecule - a non-superimposable mirror reflection. In essence, enantiomers are the "same" molecule, and can be converted into each other under certain conditions (see image below).

The virus' surface is a lipid membrane, embedded with proteins seen in the diagram above (membrane proteins, spike proteins, etc.). The proteins are crucial in allowing the virus to attach to certain surfaces in our body, and hence infect our cells. The inner genetic material (viral RNA) is released into our cells after protein attachment, allowing the virus to replicate using our cells as a host.

The lipid membrane is the most crucial to the virus' integrity - without a membrane, the protein and genetic information have no structure, and hence no way of transporting themselves throughout the body and into our cells. The membrane consists of two layers (a 'bilayer') of phospholipids, which are polar molecules that line up tail-to-tail, with their hydrophilic "heads" lining the surface of the membrane and hydrophobic "tails" tucked into the middle. This bilayer essentially forms the shape of the virus, keeping its proteins on the surface and its genetic material contained.

Similarly, soap comprises of molecules called "surfactants", whose structure bears a striking resemblance to phospholipid molecules in the viral membrane. Much like phospholipids, surfactants have a hydrophilic "head" group and a hydrophobic "tail".

When we measure the intake of common psychoactive substances (THC, cocaine, ketamine, etc.) we tend to make measurements in milligrams. It makes sense to us that, given the body mass to substance mass ratio, one would need a substantial amount of a psychoactive drug to significantly alter his or her behaviour.

However, a surprising outlier that we encounter here is LSD, or Lysergic Acid Diethylamide - an incredibly powerful psychedelic drug typically associated with causing strange visions or hallucinations. LSD, unlike any other typical psychoactive  substances (including other psychedelics), is measured in micrograms (μg) - a thousandth of a milligram. In fact, a standard dose of LSD is anywhere from 100 - 150 μg. This may strike us as unusual: how can a drug be so potent as to have an effect on the human brain in such small quantities?

To put it shortly, the secret lies in the stereochemistry of the molecule: the orientation which certain atoms in the molecule assume in space.

Firstly, to understand this better, we must consider the receptors which the LSD molecule targets.

LSD, once in the bloodstream, binds to a multitude of receptors to produce various effects. However, most importantly, (and most relevant to the "LSD experience"), the molecule binds to the 5-HT2A receptors on cortical pyramidal cells which make up the brain's cortex. These cells are the 'key computational units' in the cortex which process sensory information, and their 5-HT2A receptors are responsible for forming a complex with "happy hormone" serotonin to bring about various changes in cortical signalling.

LSD, a significantly bigger and more rigid molecule than serotonin, binds to these receptors very differently. The specialised binding of LSD to these receptors causes the top of the receptor to cave in on itself, forming a "cap" on the molecule and securing its position in the receptor. This change in receptor shape recruits a very important biological molecule: β-arrestin, which is the cause of various changes in the perceptual system (which we may go into greater detail about in a later post). Already, we can see partially why an LSD trip is so long: the molecule is trapped in the 5HT2A receptors for hours on end, causing changes in cortical signalling for a prolonged period of time. Keep this information in mind as we explore the structure of the molecule in greater detail.
​
Next, let us take a look at the shape of the LSD molecule.

The molecule body is composed of 4 rings, two nitrogen atoms as well as a carboxylic acid group. Our main focus in the exploration of LSD potency, however, will be the two ethyl groups (C2H5) found at the top left of the molecule pictured.

The ethyl groups bonded to the nitrogen are free to move around in space, and hence have the freedom to bind to the 5HT2A receptor in a very specific position.

In fact, research by Professor David Nichols, PhD., has illustrated just how important these ethyl groups are to LSD potency. Nichols conducted an experiment with four stereoisomers of LSD where the ethyl groups were fixed in specific regions of space, unable to move and adapt to the shape of the receptor.

The isomers were included one LSD molecule with up,up- ethyl groups, one with up,down- ethyl groups and one with down,down- ethyl groups, as well as the original LSD molecule with flexible ethyl groups. Nichols conducted tests with each stereoisomer on the human brain, and obtained some surprising results.

Nichols found that the isomers with fixed ethyl groups recruited significantly less arrestin per microgram, with one stereoisomer recruiting as little as 100x less arrestin than the original molecule. As seen on the graph, however, one stereoisomer had a relatively similar arrestin bias to the original LSD molecule. Upon closer analysis, Nichols found that this isomer, S,S-azetidide, had a 90% similarity in ethyl group orientation to the LSD molecule when associated with the receptor.

This revealed something very valuable to Nichols: the position of the ethyl groups largely dictates how potent LSD is. If the molecule with the most similar ethyl group orientation to LSD associated with the receptor is the most potent of the isomers, then the way the ethyl groups align with the receptor's structure is key to how potent the molecule is.

If we think back to the receptor's "cap" effect on the molecule, it becomes even more clear to us why these ethyl groups determine LSD potency. The amino acid which acts as the "cap" on the receptor is leucine-229, which has a very specific, fixed R-group structure. For the cap to properly fix on top of the molecule, the ethyl groups must orient themselves in the correct position, which can be done very easily given the free movement of these groups on the original molecule. As ethyl group orientation is fixed and becomes less and less suited to the leucine molecule on the stereoisomers, the receptor can less successfully form its "cap" on the LSD molecule and hence cannot cause sufficient cortical signalling via ​the recruitment of β-arrestin.

It is extremely atypical to find, in chemistry, a case where ethyl groups are so important to a molecule. Ethyl groups are often viewed as rather inconsequential in the function of molecules in pharmaceutical drugs, and yet, in LSD, serve as one of the most important parts of the molecule.

Therefore, the stereochemistry of an LSD molecule may not be something that we may consider important upon first glance, however, it is greatly responsible for the incredible potency that the psychoactive drug is known for today.

sources:
the research of David Nichols, PhD
David Nichols - Psychedelic Neuroscience: LSD gives up a secret