This is a ball and spoke representation of the minimum energy conformation of protonated LSD. 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. Superimposed on the electron density surface of the molecule is the molecular electrostatic potential. Red regions represent negative areas (e.g. around the amide carbonyl) while positive regions are shown as more blue (e.g. around the protonated nitrogen atom).
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.
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.
This is a representation of the LSD molecule docked inside the proposed ligand recognition site of the human serotonin 5-HT2A receptor, which is one member of the large family of G-protein coupled receptors. The receptor has been modeled using bacteriorhodopsin as a template and the alpha helical backbone is represented by the yellow ribbons. The receptor view is from the outside of the membrane, and the helices are arranged in a counter-clockwise direction. The LSD molecule is green and white, and is visible on the interior of the helical bundle. It is not known exactly how ligands bind to their recognition sites in G-protein coupled receptors. However, in all the monoamine neurotransmitter receptors, there is an absolutely conserved aspartate residue about one-third of the way down helix III from the exterior of the membrane that is believed to bind to the charged amine of the transmitter molecule. In this illustration, the basic nitrogen of LSD has been oriented toward that aspartate residue. The carbonyl oxygen of the amide group in LSD is visible as the red sphere on the "top" of the LSD molecule; the interaction with the basic nitrogen of LSD occurs on the opposite side of the LSD molecule from the carbonyl oxygen. Thus, helix III is at the bottom of the figure, helices IV and V are to the right, with the carbonyl oxygen of LSD directed toward helix VI.
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.
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.
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.
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?
Graphics and text courtesy
The Heffter Research Institute