Sunday, December 06, 2015

Theoretical studies of the LSD HOMO energy

The highest occupied molecular orbital (HOMO) energies of hallucinogen drugs have been investigated. Relationships have been shown between molecular orbital parameters and hallucinogen dose. Perhaps these relationships are shown most clearly in the panel of hallucinogenic amphetamines studied by Kang and Green in 1970.

In a classic paper in 1965, Snyder and colleagues calculated the HOMO energies of several hallucinogens using the Huckel method. Table 4 below lists the HOMO energies found for LSD, psilocin, and 2,4,5-trimethoxyamphetamine (TMA-2). It seems that the authors borrowed the Ehomo value (HOMO=0.218) for LSD from Karreman et al.


Psilocin (Ehomo=0.4603), LSD (Ehomo=0.2180), TMA-2 (Ehomo=0.4810), and TMA (Ehomo=0.5357) had a more energetic HOMO as compared to the non-hallucinogenic drugs tyramine (Ehomo=0.7209), dopamine (Ehomo=0.6586), and phenyethylamine (Ehomo=0.8619). 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 (Ehomo=0.473) and 6-methoxy-indole (Ehomo=0.489) in terms of its electron donor ability. The authors found that 4,5-dimethoxy-indole (Ehomo=0.465) would be a good electron donor, but they cast doubt on whether the value of Ehomo=0.218 for LSD is correct.

In 1970, Kang and Green calculated the HOMO energy of 13 psychotomimetic amphetamines, using the INDO (intermediate neglect of differential overlap) method, which is different from the Huckel method. Table 1 lists the HOMO energy, referred to as Eh, of the hallucinogenic amphetamines. The most potent drugs had a smaller Eh value in terms of being less negative, and there was a linear correlation between Eh and hallucinogenic activity in man.


Kang and Green reported Eh values for N,N-DMT (Eh=-0.4745) and LSD (Eh=-0.4745) in the table below. One interesting feature about this research is that negative values for Eh were obtained, which were unlike the Ehomo(beta) values reported by Snyder. Perhaps it was because of the INDO method being used.


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. The drug 2,5-dimethoxy-4-methyl-amphetamine (DOM, Eh=-0.4929) was predicted to be less potent than psilocin or LSD, according to its Eh. The drugs were distinguished from each other by only hundredths of an atomic unit, but overall, these authors were successful at correlating the actions of hallucinogens agents with Huckel molecular orbital calculations.

Snyder's data was reproduced by Nieforth (Table below) in a review written in 1971, about HOMO energy and hallucinogens.


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.

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


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 appeared summarizing the topic of charge-transfer complexes of receptors with hallucinogens. Kolb wrote,
“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)
It is well-known that hallucinogen dose is correlated with affinity to 5-HT receptors, but within this index are other relationships that may be more directly related, such as 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 going to be related to the HOMO energy of the electron donor molecule involved in the charge-transfer reaction. Hydrophobicity and steric factors are incorporated within the index of receptor binding as well, but some minimum level of HOMO energy must be necessary for hallucinogenic activity or the trends with the HOMO energies would not have been noticed. Thus, the molecular orbital calculations of hallucinogen molecules do support a charge-transfer mechanism of action of hallucinogenic drugs.



Reference

Karreman G., I. Isenberg and A. Szent-Gyorgyi (1959). On the mechanism of action of chlorpromazine. Science 130, 1191-1192.

Snyder S. H. and C. R. Merril (1965). A relationship between the hallucinogenic activity of drugs and their electronic configuration. Proceedings of the National Academy of Sciences U. S. A. 54, 258-266. doi:10.1073/pnas.54.1.258

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. Journal of Medicinal Chemistry 11, 207-211. doi:10.1021/jm00308a003
 
Kang S. and J. P. Green (1970). Steric and electronic relationships among some hallucinogenic compounds. Proceedings of the National Academy of Sciences U. S. A. 67, 62-67. doi:10.1073/pnas.67.1.62

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

Nieforth K. A. (1971). Psychotomimetic phenethylamines. Journal of pharmaceutical sciences 60, 655-665. doi:10.1002/jps.2600600502

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

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