Theoretical studies of the LSD HOMO energy

The highest occupied molecular orbital (HOMO) energies of hallucinogens have been thoroughly investigated, experimentally as well as theoretically. There is a direct relationship between molecular orbital parameters and hallucinogenicity. It is well-known that hallucinogen dose is correlated with the affinity to 5-HT receptors, but within this index are other relationships more directly related, in this case, the HOMO energy of the hallucinogen molecule. Receptor affinities reflect the likelihood of formation of a charge-transfer complex between drug and receptor, and these charge-transfer energies are directly related to the HOMO energy of electron donor molecules, or in this case, hallucinogen molecules. Other factors such as hydrophobicity and steric factors are incorporated within the index of receptor binding as well, but some minimum level of HOMO energy is necessary for hallucinogenic activity. Here is a chronological review of the research on HOMO energies of hallucinogen molecules.

In 1965, Snyder and colleagues calculated the HOMO energies of several hallucinogens using the Huckel method. Table 4 below lists the HOMO energy for LSD, psilocin, and TMA-2. The authors used the value (HOMO=0.218) obtained by Karreman and Szent-Gyorgyi for the LSD HOMO energy.

From Hallucinogens HOMO, charge-transfer

Psilocin, LSD, TMA-2, and TMA had a more energetic HOMO compared to the non-hallucinogenic drugs tyramine, dopamine, and phenyethylamine. Snyder and colleagues concluded that there is a relationship between hallucinogenic activity and the ability to donate electrons, as indicated by the energy of the HOMOs.

In 1968, Millie and colleagues investigated the HOMO energy of 1-methyl-LSD. They report Ehomo=0.487 for 1-methyl-LSD, thus placing 1-methyl-LSD somewhere in between 4-methoxy-indole and 5-methoxy-indole in terms of its electron donor ability. To my knowledge, Millie, Kang and Green, and Karreman and Szent-Gyorgyi are the only authors that have calculated the Ehomo for LSD-type molecules.

In 1970, Kang and Green calculated the HOMO energy of 13 psychotomimetic amphetamines, using the INDO (intermediate neglect of differential overlap) method, which is superior to the Huckel method. Table I lists the HOMO energy, Eh, of the hallucinogenic amphetamines. The most potent drugs had a smaller Eh value. There was a linear correlation between Eh and hallucinogenic activity in man.

From Hallucinogens HOMO, charge-transfer

Kang and Green also reported the Ehomo value for N,N-DMT and LSD, in Table 1 (below).

From Hallucinogens HOMO, charge-transfer

In Kang and Green's research, the compound 4-hydroxy-N,N-DMT (psilocin, Eh=-0.4493) was predicted to be more potent than LSD (Eh=-0.4745) going by Eh value alone, but overall, these authors were successful at correlating the actions of hallucinogens agents with Huckel molecular orbital calculations.

In 1971, Nieforth wrote a review about HOMO energy and hallucinogens, which copied Snyder's 1965 data.

From Hallucinogens HOMO, charge-transfer

Nieforth concluded that electronic energy parameters were not the only factor involved in the biological activity of hallucinogens, since other compounds such as chlorpromazine are powerful electron donors and do not possess hallucinogenic activity. (5)

By 1979, another review on hallucinogen HOMO energies appeared, which reproduced Snyder's 1965 data yet again.

From Hallucinogens HOMO, charge-transfer

Gupta verified the conclusion that there is a highly significant correlation between Ehomo and hallucinogenic activity, but he suggested that a charge-transfer phenomenon may not be the only factor responsible for the biological activity of the drugs. According to Gupta, the theory of charge-transfer formation does not fully explain drug potency in the case of anesthetic drugs.

By 1987, another review summarized the charge-transfer complexes of receptors with hallucinogens.

“In hallucinogens the electron transfer is considered to be an outer-sphere, charge-transfer process. An overall electrostatic interaction with the receptor is envisioned as a result of the charge transfer from the aromatic portion of hallucinogens to their putative receptors. .. The hallucinogenic activity of phenyl alkyl amines, indole alkl amines, and LSD was first linked to the electron transfer ability of these drugs almost three decades ago. Huckel molecular orbital calculations of a series of hallucinogenic drugs and their nonhallucinogenic structural analogues indicated the close relationship between the HOMO energy, an index of electron-donating ability, and the hallucinogenic potency. Based on these results, an electron donation model of interaction between hallucinogenic drugs and their putative receptors was proposed. Later, a series of more sophisticated molecular orbital calculations confirmed the trends initially observed with the simple Huckel method. The HOMO energies of hallucinogens were also assessed experimentally, via measurements of ionization potentials and charge-transfer capabilities of these drugs. A good agreement was obtained between the calculated and the experimentally-deduced HOMO energies.” (Kolb,V.M., 1987)

The HOMO energy, which is an index of electron-donating ability of a molecule, has been studied because of its relation to the threshold dose of hallucinogen drugs. The HOMO energy reflects the compounds’ ability to donate electrons in a charge-transfer type of interaction, thus molecular orbital calculations of hallucinogen molecules support a charge-transfer mechanism of action of hallucinogenic drugs.

References

1. Snyder S. H. and C. R. Merril. (1965). A relationship between the hallucinogenic activity of drugs and their electronic configuration. Proc.Natl.Acad.Sci.U.S.A. 54, 258-266. doi:10.1073/pnas.54.1.258

2. Millie P., J. P. Malrieu, J. Benaim, J. Y. Lallemand and M. Julia. (1968). Researches in the indole series. XX. Quantum mechanical calculations and charge-transfer complexes of substituted indoles. J.Med.Chem. 11, 207-211. doi:10.1021/jm00308a003

3. Kang S. and J. P. Green. (1970). Steric and electronic relationships among some hallucinogenic compounds. Proc.Natl.Acad.Sci.U.S.A. 67, 62-67. doi:10.1073/pnas.67.1.62

4. Kang S. and J. P. Green. (1970). Correlation between activity and electronic state of hallucinogenic amphetamines. Nature. 226, 645.

5. Nieforth K. A. (1971). Psychotomimetic phenethylamines. J.Pharm.Sci. 60, 655-665. doi:10.1002/jps.2600600502

6. Kolb V. M. (1987). Electron-transfer and charge-transfer clastic binding hypotheses for drug-receptor interactions. Pharm.Res. 4, 450-456. doi:10.1023/A:1016415202819

Indole charge-transfer complexes

What is a charge-transfer complex? It is an assembly consisting of an electron donor and electron acceptor molecule. The electron donor possesses a weakly bound electron or pair of electrons, and the electron acceptor has vacant orbitals. Electrons may come to be shared between the acceptor and donor, where they were not shared before. When a single electron participates in the transfer, the transferred electron goes from the highest filled orbital of the donor to the lowest empty orbital of the acceptor. The resulting charge-transfer complex can be a strikingly different color than the reagents.

5-HT is an exceptional electron donor. It tends to have the effect of shifting the outer shell electrons from one molecule to another, thus 5-HT has the propensity to form donor-acceptor complexes with electron acceptors such as picric acid. In the formation of serotonin-picrate crystals, serotonin is the donor molecule and picrate is the electron acceptor. A red-colored charge-transfer complex is formed when serotonin is added to picric acid.

The geometry of charge-transfer electronic transitions has been studied with crystal structures of serotonin-picrate. In serotonin-picrate crystals, the nitro groups of picric acid interact with C2 and C3 of the indole ring, suggesting that the nitro group of the electron acceptor associates with the pi electron cloud of 5-HT.

"It is significant that the observed geometry is such that charge-transfer electronic transitions apparently can occur and impart color to the [red serotonin picrate] crystals." (C.E. Bugg, 1970)

Indoles in general form charge-transfer complexes. The exceptional electron-donating ability of the indole nucleus is related to a high-lying pi electron on the carbon atom at position-3 of the indole donor. Serotonin, tryptophan, aminotryptophan, and methoxytryptophan all function as electron donor molecules in the formation of charge-transfer complexes. These indole donors can pair with electron acceptor molecules of biological importance, such as riboflavin, nicotinamide, or DPN.

Tryptophan is an indole derivative, and it is a better electron donor than most aromatic amino acids, thus proteins are known to participate in charge-transfer reactions via their tryptophan residues. When tryptophan is mixed with riboflavin, and cooled to -78 C, a strong red color is observed. Tryptophan also forms a visible charge-transfer complex with electron acceptors DPN+ or TPN+. At the temperature of dry ice, tryptophan-DPN+ and tryptophan-TPN+ complexes had a yellow color, with strong absorption in the region of 400 nm.

Overall, serotonin is a better electron donor than tryptophan. This has been shown theoretically by calculating the kHOMO energy of 5-HT and tryptophan, and experimentally by mixing 5-HT or tryptophan with the same electron acceptor, riboflavin. 5-HT and tryptophan both form charge-transfer complexes with riboflavin but serotonin complexes much more strongly, thus it has been verified that serotonin is a better electron donor than tryptophan. The physiological properties of 5-HT might be related to the exceptional electron donor capabilities of the hydroxyindole moiety.

Coming to the present topic, LSD is an extremely good electron donor with kHOMO=0.218-0.487, which has been shown to form charge-transfer complexes with small molecules such as riboflavin, TCNE, and dimethylaminobenzaldehyde. Also, LSD forms charge-transfer complexes with electron acceptor macromolecules, such as wool protein, dopamine receptors, and 5-HT2A receptors. It has long been suspected that psychoactive drugs, including chlorpromazine and phenothiazine derivatives, function as electron donors in a key step involving charge-transfer interactions. Drugs may donate or accept electrons, disrupting the normal pathway for electron transport and thus interfering with oxidation-reduction processes such as the respiration chain.



References

Bugg C. E. and U. Thewalt. (1970). Crystal structure of serotonin picrate, a donor-acceptor complex. Science. 170, 852-854. 10.1126/science.170.3960.852

Isenberg I. and A. Szent-Gyorgyi. (1959). On Charge Transfer Complexes between Substances of Biochemical Interest. Proc.Natl.Acad.Sci.U.S.A. 45, 1229-1231. 10.1073/pnas.45.8.1229

SZENT-GYORGYI A., I. ISENBERG and J. McLAUGHLIN. (1961). Local and pi-pi interactions in charge transfer. Proc.Natl.Acad.Sci.U.S.A. 47, 1089-1094. 10.1073/pnas.47.8.1089