A Comparison of Serotonin and Lysergic Acid

John Bowman and Mike Trinh

Table of Contents

  1. Purpose of the Project
  2. Scientific Background
  3. Computational Approach
  4. Results
  5. References

Purpose of the Project

Using the methods of computational chemistry, the structure of the neurotransmitter serotonin was analyzed. This structure was compared to that of lysergic acid, a chemical that bonds to the same receptor as serotonin in the brain to produce a hallucinogenic effect. This purpose of this project was to determine why lysergic acid bonds to the same receptor, yet produces a different effect than serotonin.


Serotonin (on the left) and Lysergic Acid ( on the right)

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Scientific Background

Serotonin, or 5-Hydroxytryptamine, is a neurotransmitter, carrying neural messages from nerve cell to nerve cell. Imbalances in Serotonin can result in migraines, depression, and exhaustion. High serotonin levels have been associated with REM sleep.

Lysergic acid is a metabolite of LSD, a hallucinogenic drug. Lysergic acid and similar compounds, collectively known as serotonin antagonists, bond to the same D-receptors used by serotonin. Through this action, lysergic acid blocks serotonin and redirects neural pulses.

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Computational Approach

MacSpartan, a molecular modeling tool, was used to build models of both serotonin and lysergic acid. The geometry of serotonin, the smaller molecule, was optimized using the 3-21G ab initio basis set. The complex lysergic acid molecule could be processed by this method within a reasonable time. Instead the geometry was computed with the semi-empirical AM1 method. After optimization the two molecules were compared with respect to electrostatic potential and LUMO (lowest occupied molecular orbital, a measure of electron affinity). Further, the resonance frequencies of the two molecules were analyzed and compared.

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Results


Master Data Chart

Electrostatic Potential is given in kcal/mol, energy and LUMO in hartrees, dipole moments in debyes
Electrostatic Potential LUMO Energy Dipole
Top Edge Top Edge (Hartrees) (Debyes)
Serotonin -29.0 61.0 0.0257 0.0 -566.242 3.86
Lysergic Acid -28.0 40.80.0116 0.0 -0.0172 5.50

Geometric optimization of the serotonin molecule gave a structure with an energy of -566.242 hartrees, indicating a stable configuration. Optimization of lysergic acid by empirical methods gave an energy of -0.001715 hartrees. The lysergic acid molecule produced was therefore only maginally stable.

Portions of the serotonin and lysergic acid molecules are identical. Each has a phenyl ring. One side of the ring is encorporated into a pentagonal ring of four carbons and a nitrogen, with two carbons connected by a double bond. Looking at this region in both molecules using computational methods, one finds many similarities.

The electrostatic potential representations below show a clam-shell-like region of electron concentration above and below the phenyl and nitrogen ring structures in both molecules. In the areas where the two molecules did not resemble one another, the electrostatic potentials differed greatly. There was a strong positive electrostatic potential along the edge of the common ring structures in both molecules. Above and below the plane of the ring structures, there was a strong negative electrostatic potential. These strong potentials indicate the regions would be likely sites for attachment to a receptor site in the brain. Serotonin had stronger potentials (both higher positive and lower negative potentials), indicating that it might be attracted more strongly to a charged receptor site.


Electrostatic potential surfaces of Serotonin (on the left) and Lysergic Acid ( on the right)


Serotonin at a different perspective

The LUMOs (lowest unoccupied molecular orbitals) of serotonin and lysergic acid were very similar near the phenyl and nitrogen ring. These orbitals show a high electron affinity in the regions above and below the common regions. However, in general electron affinity was higher for this structure in serotonin than in lysergic acid. The region may be responsible for bonding to the receptor in both molecules.


LUMO displays of serotorin (On the Left) and lysergic acid (On the Right)

Lysergic acid and serotonin share similarly oriented dipoles, though the magnitude of the lysergic acid dipole is greater.

This data shows that the two ring structures present in both the serotonin and lysergic acid structures likely allows the two molecules to attach to the same D-receptor site in the brain. However, the two molecules are different enough that serotonin causes a neuron to transmit their electric impulses in a normal fashion while lysergic acid blocks serotonin attachment and redirects neural pulses, causing others to fire unpredictably. The end result is a state of hallucination.

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References

Goth, Andres. Medical Pharmacology: Ninth Edition. St. Louis: C.V. Mosby Co. 1975.

Modell, Walter et. al. Applied Pharmacology. Philadelphia: St. Louis: W. B. Saunders Co, 1976.

Mcclay, Russ. "The Pineal Gland, LSD and Serotonin." Online. Available: http://www.magnet.ch/serendipity/mcclay/pineal.html#a1.6. 14 April 1997.

Timmons, C. Robins amd Hamilton, Leonard W. " Pyscoactive Drugs." Online. Available: http://www.rci.rutgers.edu/~lwh/drugs/ppbl-1a.htm. 14 April 1997

Gotwals, Bob. "Computational Chemistry." Personal Conversations. 11-15 Aug. 1997

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