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A Primer on Skeletal Structures, Molecular Nomenclature, and Psychedelic Molecules

It's very common in the psychedelic sphere to see people throw around molecular structures and fancy chemical names. If you're looking for help with reading and understanding those names and structures, then this article should help you understand the basics.

What is an organic molecule?

-Compounds containing carbon-carbon or carbon-hydrogen bonds

-They also commonly include oxygen, nitrogen, and a few other atoms

-There are some exceptions to these rules (for example, Carbon Dioxide is considered inorganic)

 

Bonding Patterns

-An atom is structured as a central nucleus consisting of protons and neutrons orbited by shells (or orbitals) of electrons. There are multiple shells which can hold increasing numbers of electrons. The first shell can hold 2 electrons. The second can hold 8. The atoms we'll be talking about today only have up to 2 shells.

-These atoms bond together via covalent bonds, which consists of the sharing of electron pairs.

-Each atom has bonding preferences based on the number of electrons in its outmost orbital (valence electrons):

 

1 shell:

-Hydrogen (H) (1 electron) = 1 bond

Because the first shell can only hold 2 electrons, Hydrogen only needs 1 more electron to complete its shell, and thus can only have one bond.

 

2 shells:

-Oxygen (O) (8 electrons) = 2 bonds

-Nitrogen (N) (7 electrons) = 3 bonds (but this one is more flexible)

-Carbon (C) (6 electrons)= 4 bonds

 

Each of these has a filled first shell of 2 electrons. This means Carbon has 4 valence electrons in its outer shell, and can accept 4 more (four bonds). Oxygen has 6 valence electrons, and can accept 2 more (two bonds).

 

Now, when looking at a molecular structure, we can assume that each atom has that number of bonds, as that is most stable. Hydrogens will always fill in the gaps - thus, if we see a carbon with 2 bonds, then we can assume that it has 2 hydrogens attached to it, as carbon will always have 4 bonds. A lone oxygen will have 2 carbons attached to it. A lone carbon will have 4 hydrogens attached to it. 2 carbons attached to each other will have 3 hydrogens attached to each of them. Etc.

 

Functional Groups

The function of a molecule is determined by certain parts which we call functional groups. Here are the functional groups we're most concerned with today:

-Methyl (R-CH3): A lone carbon, with one bond to the molecule in question (R) and 3 hydrogens filling in the rest.

 

 

-Ethyl (R-CH2-CH3): 2 carbons bonded to each other. One will have 3 hydrogens, the other has 2 hydrogens, a bond to the other carbon, and a bond to the molecule in question.

 

-Hydroxyl (R-OH): An oxygen bonded to the molecule and one hydrogen

-Methoxy (R-O-CH3): An oxygen bonded to a methyl group and the molecule. 

 

-Amino group (R-NH2): A nitrogen bonded to the molecule and 2 hydrogens

 

How to read a skeletal structure

Each point of connection between two lines is a Carbon. Each carbon is assumed to have 4 bonds, so add the number of hydrogens you need to reach 4. For example, the neurotransmitter serotonin:

                                                   =                                       =  

 

(Grey orbs are carbon, blue are nitrogen, red are oxygen, white are hydrogen)

Many of the carbons are double bonded to each other (2 lines), which is why they only have a single hydrogen attached to them.

 

 

Building serotonin

Let's put together serotonin, piece by piece. Let’s start by putting 6 carbons together in a line. That’s hexane:

 

                                                                               =

 

Now what would happen if we connected the carbons on each end to form a ring (losing one hydrogen from each end)? That’s cyclohexane:

                                                                                                 =

 

Now let’s lose half of the hydrogens from that and double bond those carbons. That’s called a benzene ring:

                                                                                                 =

A double bond is when two atoms share two pairs of electrons, instead of just one in a single bond. What we see here isn’t a totally accurate depiction - this structure doesn’t actually alternate single and double bonds. Instead, the electrons are ‘delocalized’, free to move around, so all the bonds you see there are both single and double bonds - think of it as a hybrid structure:

 

This is a more accurate depiction of the molecule:

 

Benzene, a hydrocarbon, is a very common structure in organic chemistry. Benzene is a petroleum product, and quite toxic on its own. But as a component in other molecules, its effect in the body changes drastically. Let's combine it with what is called a pyrrole ring:

Put the two together, and you get what is called an indole ring:

 

This is no longer a toxic substance in small quantities. In fact, it is largely responsible for the odor of feces, alongside skatole, which has an additional methyl group (CH3 - remember, one carbon and its associated hydrogens) substituted at the second carbon (which was was formerly attached to a hydrogen):

 

 

Amusingly enough, indole and skatole have a floral smell at lower concentrations, and thus is used in many perfumes. It is produced by many bacteria as an intercellular signaling molecule.

Now let's take indole and substitute an aminoethyl group (exactly what it sounds like - a nitrogen bonded to a 2-carbon chain) at the 2nd carbon, instead of a methyl group:

 

This is tryptamine, a metabolite of tryptophan. It serves a number of functions in the body, activating trace amine receptors, regulating the activity of dopaminergic, serotonergic, and glutaminergic systems, and regulating gastrointestinal motility. It is also the shared structural underpinning of serotonin, melatonin, psilocybin, psilocin, bufotenin, DMT, 5-MeO-DMT, and many others! Let's take another look at that molecule and give each carbons a number:

Each of those numbers represents a position. There is a hydrogen attached at each of those numbers, but it can be removed and replaced with a functional group, which will change what the molecule does in the body.

 

So, how do we get to serotonin from tryptamine? Stick a hydroxyl group (HO - a hydrogen and an oxygen) at the 5 position, as seen on the previous slide. The result is 5-hydroxytryptamine (5HT), otherwise known as serotonin! Let's take another look at it:

 

 

 

Let's do something else with tryptamine instead. What if we replace the hydrogens attached to that nitrogen at the end of the amino ethyl group with methyl groups?

 

 

This is N,N-dimethyltryptamine, otherwise known as N,N-DMT or DMT. It is an endogenous molecule that may be a neurotransmitter in its own right, in addition to being one of the most powerful psychedelic drugs, found in thousands of plant and animal species. Given how similar the structures of serotonin and DMT are, it's no surprise that DMT is able to fit in serotonin receptors! Now take another look at that name - dimethyl. Di- means 2, so we have 2 methyl groups, which are the most basic functional groups (one carbon and 3 hydrogens). N,N is a position marker, meaning in this case that they are both attached to the nitrogen. So the name is almost like a set of instructions - take tryptamine and substitute the hydrogens attached to the nitrogen with 2 methyl groups. Is the nomenclature beginning to make sense?

 

Now let's try out some substitutions to find other psychedelic drugs. First, let's try putting a hydroxyl group on the 5 position, like we did to get serotonin from tryptamine above:

 

 

This is 5-hydroxy-N,N-dimethyltryptamine (5-HO-DMT), otherwise known as bufotenin. It is also an endogenous molecule, and is a psychedelic substance that can be found in the seeds of yopo and cebil/vilca.

 

Let's replace that hydroxyl group with a methoxy group (a methyl group attached to an oxygen):

 

This is 5-MeO-DMT, the third endogenous psychedelic molecule and possibly the most powerful of them all - albeit quite different from the other two, with a thousandfold higher binding affinity for 5-HT1a than 5-HT2a. Like N,N-DMT and 5-HO-DMT, it is also a ubiquitous molecule in nature and endogenous in humans. It can be found in high concentrations in the resin of the virola tree and the venom of the Sonoran Desert Toad.

 

Now let's go back to bufotenin for a second. What if we move the hydroxyl group from the 5 position to the 4 position? We get 4-HO-DMT, otherwise known as psilocin, the main active compound in magic mushrooms:

 

 

 

And yet it isn't psilocin you're always hearing about - it's psilocybin (4-PO-DMT). Why is that?

 

 

 

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) cannot cross the blood brain barrier. The liver dephosphorylates it, chopping off the phosphoryl group (the phosphorus and everything attached to it):

 

...and replacing it with a hydrogen, leaving us with psilocin. There is some psilocin in mushrooms, as well, but it's a more unstable compound - thus, psilocybin is better for long term storage and is usually found at higher amounts in mushrooms.

 

The body may do the same thing with the synthetic compound 4-AcO-DMT (psilacetin). 4-AcO-DMT is shorthand for 4-acetoxy-N,N-dimethyltryptamine. So, an acetyl group (defined momentarily) attached to an oxygen, all attached to DMT at the 4 position:

 

 

The functional group at the 4 position is called an acetoxy group. Part of that, called an acetyl group, gets chopped off in the liver and replaced by a hydrogen, again yielding psilocin.

 

 

Psychedelics are some of the best existing treatments for cluster headaches. As such, efforts have been made to develop variations on psychedelic molecules that abort cluster headaches without psychedelic effects. For example, here is Sumatriptan - it's DMT with a more complex functional group at the 4 positions:

So, we've now looked at 4 psychedelic compounds - N,N-DMT, 5-MeO-DMT, bufotenin (5-HO-DMT), and psilocin (4-HO-DMT). All of these share a strong enough structural similarity to serotonin to fit in the same receptors, but since they have different functional groups, they each interact with those receptors a little differently and thus have distinct characteristics. It's the functional groups that make all the difference and ultimately determine the effects. How these molecules interact with the receptors they bind to is very complex, and not easy to predict just by looking at their structures! This is why it's necessary to conduct trials to determine the effects of various molecules in the body. Some substituted tryptamines have psychedelic effects. Others are neurotoxins. Others have serotonin releasing activity (similar to MDMA), or MAO inhibition properties (like the harmala alkaloids in ayahuasca vine, or old school antidepressants). Melatonin is a sleep hormone, and serotonin is a neurotransmitter. A small change in molecular structure can have a massive change on its molecular properties and its effects in the body!

 

For a potent example of this, take vinegar - otherwise known as acetic acid (CH3-COOH). Now let's substitute one of the hydrogens in that methyl group (CH3) with a fluorine (F). The result is Fluoroacetic acid (CH2F-COOH), a very strong poison often used to manufacture rodenticides. A difference of just one atom turns a molecule from something you can put in your dinner to something that will kill you!

 

For a practical psychedelic example, because popular culture doesn't refer to mushrooms using DMT in the name, nobody confuses the two substances. But people do look at 5-MeO-DMT and confuse it with N,N-DMT, since they can both be vaporized and both have DMT in the name. The proper dosages for these two substances are very different, as are the experiences they elicit. DMT, for all practical purposes, cannot kill you - but 5-MeO-DMT can. You need much smaller amounts of 5-MeO-DMT, and large doses can be dangerous. I think you can see why it's important not to mix these things up!

 

----

 

Now let's look at another molecule that forms the backbone of neurotransmitters - phenethylamine, which contains a benzene ring and an aminoethyl group, much like tryptamine, but lack the pyrrole ring between them:

 

Phenethylamine acts as a CNS stimulant in humans and regulates neurotransmission, also acting as a neurotransmitter itself to some extent. It's also found in chocolate and sold as a supplement.

Add hydroxyl groups at the third and fourth positions, and you get dopamine (3,4-dihydroxyphenethylamine). So, di (two) hydroxyl groups attached to phenethylamine at the 3rd and 4th positions:

 

Other substituted phenethylamines include epinephrine (adrenaline), phenylephrine (the OTC nasal decongestant), ephedrine, pseudoephedrine, and the amphetamines (including MDMA) and substituted cathinones (including buproprion, the antidepressant).

 

The most well known psychedelic phenethylamine is mescaline - 3,4,5-trimethoxyphenethylamine, found in many species of cacti, like peyote and huachuma. Let's dig into that prefix. We learned earlier that a methoxy group is a methyl group (a carbon with 3 hydrogens) attached to an oxygen. 3,4,5-tri - ok, so we've got 3 methoxy groups placed on phenethylamine at positions 3, 4, and 5:

 

It's so similar to dopamine, and yet it mainly acts on serotonin receptors!

 

So, how about LSD-25 - lysergic acid diethylamide?

 

Going back to that functional groups principle, lysergic acid itself is not psychedelic:

 

The single bonded oxygen (a hydroxyl group!) is replaced by a nitrogen attached to two ethyl groups to form diethyl amide, yielding LSD. Let's break that term down - diethyl means there are are 2 ethyl groups (the CH3s). Those are attached to an amide, which is a nitrogen bonded to a carbon which is double bonded to an oxygen.

 

LSD is a bigger, more complex molecule than anything else we've looked at thus far, but if you look closely, you'll find the structure of DMT hidden in there, albeit with several new bonds:

 

 

So LSD must be a tryptamine, right? But look again, and you'll see a phenethylamine backbone buried in there as well:

 

LSD is thus in its own class of molecules - ergolines, or lysergamides. It contains elements of the structure of both of the previous classes we discussed. The tryptamine structure is more prominent, but LSD also affects dopamine - perhaps that has something to do with its relationship to phenethylamine!

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