Graphic Representations of Psychedelic Drug Molecules

[Expat98]

I found the graphics and information below on the website of the Heffter Research Institute, which was founded by David Nichols, a longtime researcher on the chemistry of psychedelic drugs and a colleague of Alexander Shulgin.



Serotonin & Psilocin

You are the receptor. Two molecules are diffusing through the aqueous environment, facing you. On the left is a protonated molecule of the neurotransmitter serotonin (5-hydroxytryptamine). On the right you "see" a molecule of protonated psilocin (4-hydroxy-N,N-dimethyltryptamine). How do you choose which one to bind? They really look so similar. Yes friends, they do look quite a bit alike. In fact, the chemical similarities between DMT, psilocin, and even LSD, and the structure of the natural neurotransmitter serotonin led to the idea that hallucinogens might interact with brain serotonin receptors. In the graphic this week, we present energy minimized structures of serotonin, on the left, and psilocin, on the right. Both structures are protonated, as they would be at physiological pH. As in earlier graphics, the ball and stick structures are surround by a grid representing the molecular electrostatic potential, where blue areas are more positive, and red areas are more negative. We can see that both side chain nitrogen atoms are surrounded by positive regions, as a consequence of the positive charge brought by the proton. This charge is spread out over the two N-methyl groups in psilocin so that the positive charge isn't so "concentrated" around the nitrogen. Although not completely evident, the region around the hydroxy group of psilocin is less negative (less red) as some of this charge is neutralized by the close proximity of the positively charged amino group. Both indole rings are also negative, and indole is generally considered to be a pi electron exessive aromatic system. So, what do we have, one hydroxy group moved, and methyl groups attached to one molecule's nitrogen atom. One is hallucinogenic, the other is not. Or is it?



5MeoDMT

This figure is a representation of the minimized structures of 5-methoxy-DMT free base (on the left) and its protonated form (on the right). Again, these were minimized using the semi-empirical methods employed in the Spartan software package, with the AM1 Hamiltonian. The free base was minimized in vacuum, while the protonated molecule was minimized in water. The electron density surface is plotted as a mesh, with the molecular electrostatic potential mapped on the surface. Blue regions are positive, while red regions are negative. On the upper left part of the molecule, the electron pair of the free base imparts negative character to the potential surface, while in the protonated form, this area is quite positive (as reflected by the blue color). The relatively more negative regions around the methoxy oxygen and the pi surfaces of the aromatic indole ring system are more evident in the protonated molecule on the right. 5-Methoxy-DMT is a component of several snuffs used by Amazonian Indians and is reported to have a very brief duration of action, but there is actually very little literature concerning the clinical effects of this material. Anecdotal reports suggest, however, that low doses, administered by smoking or nasal insufflation, are highly anxiogenic and unpleasant, while larger doses can produce an overpowering experience that involves ego loss and the feeling that one has died. Like the other tryptamines, this compound is known to stimulate serotonin receptors of the 5-HT2A and 5-HT1A subtypes.



Bromo Molecules

Here is something a bit different from the usual feature. On the left is a molecule of 2,5-dimethoxy-4-bromphenethylamine ("2C-B"). On the right is a very similar molecule. Can you see the difference? In the molecule on the right, the 2 and 5 methoxy groups have been incorporated into dihydrofuran rings. So, instead of a methoxy, which is an -OCH3, the molecule has an -OCH2CH2- which connects back to the phenyl ring. Some years ago we began to wonder what the orientation of the methoxy groups was when they bound to the receptor. This was an important question, because oxygen atoms have unshared pairs of electrons, and these can overlap with the pi system of the aromatic ring, or perhaps may serve to interact with a hydrogen bond donor within the receptor, such as a serine or threonine residue. A free methoxy group can rotate and undergo conformational movement. When we fixed the methoxys into dihydrofuran rings, like the molecule on the right above, we found that the potency of the molecule was increased! This was a sure sign that we had locked the methoxys into the conformation that they adopt at the receptor. Furthermore, it also told us that the receptor had some space next to the methoxy groups, since the dihydrofuran ring is somewhat larger than a methoxy, and occupied more space. These two molecules were energy-minimized using the semiempirical routines in the Spartan software and the AM1 Hamiltonian. The renderings are of space-filling models, overlaid with the electron density surface onto which has been plotted the molecular electrostatic potential.



DOB & DOI

These molecules are, on the left, DOB, and on the right, DOI. These are space-filling representations of the minimum energy conformations of the free bases in a vacuum. The more active R-(-) optical isomers are shown for both of them. The red atoms are in the 2,5-dimethoxy groups, and the blue atom is the amino group in the side chain. Chemically, they're really pretty similar. The only obvious difference is the brown bromine atom on DOB, and the purple iodine atom on DOI. They are both among the most potent substituted amphetamine type hallucinogens known. It has been known for many years that the most active compounds possessed 4-substitutents that were hydrophobic (nonpolar) and resistant to metabolism. Halogens such as bromine and iodine fit this requirement well. Although it is not known for certain why these groups give such high activity, one possibility is that the 4-substituent fits into a hydrophobic region in the serotonin 5-HT2A receptor. Both of these compounds have a quite long duration of action when given to man, probably because they are so resistant to metabolism. The alpha-methyl of the side chain hinders deamination, which is a minor metabolic pathway in any case, and the bromine or iodine atom blocks aromatic hydroxylation at the 4-position, which would otherwise be expected to be an important metabolic route.



Isoproscaline

The figure this week is something a little different. What is shown are two different conformations of the isoproscaline molecule. Isoproscaline is an analogue of mescaline, where the 4-methoxy group (-OCH3) has been replaced with a 4-isopropoxy group (-OCH(CH3)2). In both molecules, the isopropoxy is directed toward the "7 o'clock" position. The molecule was first of all minimized using semiempirical methods and the AM1 Hamiltonian, as employed in the Spartan software. Calculations were for the free base, and minimization was in a vacuum. This resulted in the molecule shown on the left. The molecules are rendered as their bonding electron densities. The electron density surface is over that, with the molecular electrostatic potential mapped onto that surface. It seemed a little strange that both of the -CH3 groups of the isopropoxy were directed toward the aromatic ring, so this group was rotated 180 degrees and the whole structure was then minimized to determine where the isopropyls ended up. And... they ended up where you see them in the figure on the right. This is called a "local minimum", a place where there is a sort of low energy well, but this is not the lowest energy conformation possible; that is the one shown on the left. In fact, the conformation on the left is about 4 kcal/mol more stable than the one on the right. What this means is that at ordinary temperatures the isopropoxy group in isoproscaline orients itself as shown in the structure on the left.



(+)-LSD

(5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD-25) is the most potent psychedelic agent. This is an energy minimized conformation of protonated LSD that corresponds to its structure in the crystal state.


LSD - Molecular Electrostatic Potential

The LSD molecule is rendered as an electron probability density isosurface. The color contours represent varying electrostatic potential at the surface and have been modified for aesthetic purposes. The electrostatic potential is most positive in light yellow areas, with red areas neutral, and the dark purple regions most negative. Calculations were performed on a Tektronix CAChe (TM) molecular modeling worksystem: initial molecular mechanics optimization was performed using CAChe's conjugate gradient routine with Allinger's standard MM2 force field parameters. The structure was further refined using CAChe's implemation of the molecular orbital package MOPAC using the AM1 Hamiltonian parameters. The electron density isosurface was generated using CAChe's Tabulator module.



LSD

This is another representation of the minimum energy conformer of LSD, shown as a ball and spoke model. Minimization was carried out in a vacuum, using semiempirical methods and the AM1 Hamiltonian as implemented in the Spartan software package (v. 4, Wavefunction, Inc) and running on a Silicon Graphics Indigo 2 workstation. The molecular electrostatic potential (MEP) has been mapped onto the electron density dot surface of the molecule. In addition, Spartan has been used to display the MEP as a series of energy contours, displayed on planes perpendicular to the molecular least squares plane.


LSD

This is a representation of the minimum energy conformer of LSD free base. Minimization was carried out in a vacuum (i.e. without any solvent molecules around the molecule), using semiempirical methods and the AM1 Hamiltonian, as implemented in the Spartan software package (v. 4, Wavefunction, Inc) and running on a Silicon Graphics Indigo 2 workstation. The electron density surface of the molecule is rendered as a grey mesh surface. The molecular electrostatic potential (MEP) has been plotted on the least squares plane of the molecule as a series of contour lines. Finally, volumes representing the highest occupied molecular orbital (HOMO) are also plotted on the molecule. The phases of the lobes of the HOMO are represented either as blue or red.



Mescaline

This is a representation of the minimum energy conformer of mescaline free base, shown as a ball and spoke model. Minimization was carried out in a vacuum (i.e. without any solvent molecules around the molecule), using semiempirical methods and the AM1 Hamiltonian as implemented in the Spartan software package (v. 4, Wavefunction, Inc) and running on a Silicon Graphics Indigo 2 workstation. The molecular electrostatic potential (MEP) has been mapped onto the electron density surface of the molecule (shown as a mesh surface). Blue regions are more negative, moving to more positive potential in red regions. Barely visible inside the mesh density surface, are transparent surfaces representing the highest occupied molecular orbital (HOMO) of this molecule. The phases of the lobes of the HOMO are represented either as blue or red. Very early research on psychedelics suggested that the energy of the HOMO was an important determinant of activity, although it is not clear today that this is particularly the case.



MDMA

This is the low energy protonated form of S-(+)-3,4 - methylendioxy - methamphetamine, the active isomer of MDMA.


MDMA

This is the minimum energy conformation of (+)-3,4-methylenedioxymethamphetamine (MDMA). The molecule was minimized as the free base in vacuum, using the AM1 Hamiltonian as implemented in the Spartan (Wavefunction, Inc.) semi-empirical routines. The molecular electrostatic potential has been mapped as a mesh surface onto the electron density surface of the molecule, where more negative regions are coded as red, and more positive regions as blue. MDMA differs from hallucinogens in that it works indirectly, by the release of the neurotransmitters dopamine, serotonin, and norepinephrine from neuron terminals, while the hallucinogens such as LSD stimulate receptors directly.



Psilocybin

This is an energy-minimized version of psilocybin, or 4-phosphoryloxy-DMT, the primary psychoactive component in psilocybin mushrooms, used by the Aztecs in South America as Teonanacatl, a word meaning approximately "god's flesh". The dephosphorylated molecule, 4-hydroxy-DMT, or psilocin is the active molecule. It has been shown in studies with mice that serum phosphatases rapidly cleave off the phosphate ester to generate psilocin if mice are given psilocybin. Presumably, the ubiquitous phosphatases throughout the mammalian kingdom are equally robust in humans. The phosphate ester is a little unusual in alkaloidal natural products, but it does serve to retard oxidation of the indole nucleus. Samples of psilocin when kept at room temperature slowly darken and decompose, while we know of one sample of psilocybin made about 40 years ago that has retained its purity and color after similar storage conditions. Psilocybin exists as a zwitterion, meaning that it has both negative and positive charges within the same molecule. In this ball and stick version of the molecule, the phosphate group is on the top left while the dimethylamino group is at the top right. Slices of contour plots of the molecular electrostatic potential have been plotted on top of the molecule. The red/orange regions around the phosphate reflect the negative charge that is characteristic of the phosphate anion, while the more blue regions around the amino group reflect the positive character brought by the proton (which was donated by the phosphate). Most tryptamines, such as DMT and 5-Methoxy-DMT are not orally active. It is currently believed that this is due to their rapid side chain deamination by monoamine oxidases, primarily in the liver. Although it has never been proven, it is speculated that the 4-oxygenation of psilocin interferes with this enzymatic side chain degradation, and allows the molecule to be orally absorbed. Several years ago we published a study using nuclear magnetic resonance, where we showed that there is clearly some sort of interaction between the side chain amino group and the 4-hydroxy of psilocin. The interaction is even stronger for psilocybin.


Salvinorin

his is a framework representation of a molecule of Salvinorin A, the psychoactive component of Salvia divinorum. The molecule was minimized using molecular mechanics routines, as implemented within the Spartan software package (v. 4, Wavefunction, Inc) and running on a Silicon Graphics Indigo 2 workstation. This compound, which anecdotal accounts suggest is extremely potent when administered parenterally, has an unknown mechanism of action, one that clearly differs from the classical hallucinogenic agents such as LSD or mescaline. As suggested by the large number of carbon atoms in this structure, the molecule is very lipid soluble. Curiously, salvinorin A also lacks a basic nitrogen atom, a feature that is quite uncommon among psychoactive compounds. Tetrahydrocannabinol is the only other well known psychoactive substance that lacks a basic nitrogen, but there is no evidence that these two molecules share a similar mechanism of action.



Serotonin

This is the energy-minimized (semi-empirical; AM1 Hamiltonian) protonated structure of serotonin. It is presented as a 3-dimensional representation, which can be viewed using the crossed-eyes method (Look at the screen and cross your eyes until you have multiple images. Slowly relax your eyes until there are only three images, and focus on the central one). For the purposes of the Heffter Institute, this neurotransmistter molecule is where it all started. Serotonin is a neurotransmitter that is produced principally by neurons that arise from ancient groups of cell bodies in the brain stem known as the raphe nuclei. These cells project their axons to higher centers in the brain, and are believed to regulate very basic brain functions such as appetite, sleep, anxiety and other emotions, memory, sex, etc. New generation antidepressants alter serotonin function in the brain, and the newer antipsychotic drugs possess the ability to block certain kinds of serotonin receptors in the brain. The cerebral cortex has a very high density of serotonin 5-HT2A receptors, principally located on apical dendrites of cortical neurons, and it has recently been proposed that these receptors play a key role in cognitive functions, by gating ion flows in these neurons. Well, that's no surprise, because we know that psychedelics target this same receptor, and they profoundly affect cognitive function! The role of serotonin in the brain continues to be a fascinating and intense area of research.



Psilocin

This is the low energy conformation for the unprotonated form of psilocin in a vacuum. It was calculated with the Tektronix CAChe molecular modeling worksystem. Initial molecular mechanics optimization was performed using CAChe's conjugate gradient routine with Allinger's standard MM2 force field parameters. The structure was further refined using the CAChe implementation of MOPAC using the AM1 Hamiltonian parameters.

Reputation Comments on this post:

	really really fucking awesome pics on here....great find!
	WOW. Amazing and very informative find.

[pistol pete]

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