LSD charge-transfer complexes 3. LSD-riboflavin

Hallucinogenic agents are probably electron donors in some key step involving a charge-transfer complex with a biological acceptor molecule entity. Previously I covered the topic of electrostatic and charge-transfer forces in LSD-TCNE and LSD-NAD+ small molecule complexes. This article will present studies on a LSD-riboflavin complex.

In 1958, Isenberg and Szent-Gyorgyi mixed LSD-25 with riboflavin-5'-phosphate and observed a red color at –78 C. They discovered that the riboflavin molecule had taken up one electron from LSD. LSD was functioning as an electron donor in the formation of riboflavin charge-transfer complexes; the transferred electron (e.g. to reduce riboflavin) comes from the pi-electron pool of the LSD indole system. In the same publication, the authors reported on tryptopan-riboflavin, 5-HT-riboflavin, and 1-methyl-medmain-riboflavin complexes, all of which led to the appearance of a red color at -78 C. The results are shown in Table 1 below.

From Hallucinogens HOMO, charge-transfer

Histidine-riboflavin or tyrosine-riboflavin did not give a red color, indicating that no charge-transfer complex had been formed, and that histidine and tyrosine are inferior in electron-donating ability compared to drugs such as tryptophan and LSD. There were variations among the drugs which formed a charge-transfer complex with riboflavin. For example, the 5-HT-riboflavin complex was 7X stronger than the tryptophan-riboflavin complex indicating that serotonin was a better electron donor than tryptophan.

Some tissues such as liver have a great quantity of strongly bound riboflavin. The brown color of the liver can be attributed to the flavin radical formed in a charge-transfer interaction with liver protein. If liver tissue becomes cancerous, it takes on a different balance of reductive and oxidative processes and changes color.


References

Isenberg I. and A. Szent-Gyorgyi. (1958). FREE RADICAL FORMATION IN RIBOFLAVIN COMPLEXES. Proc.Natl.Acad.Sci.U.S.A. 44, 857-862. doi:10.1073/pnas.44.9.857

LSD charge-transfer complexes 2. LSD-NAD+

The electron acceptor NAD+ forms a charge-transfer complex with LSD, in which an electron is transferred from the highest occupied molecular orbital (HOMO) of the LSD pi system to the lowest empty molecular orbital of NAD+.

The charge-transfer process is accompanied by the appearance of a new absorption band. In 1967, Fulton and colleagues studied the wavelength of the absorption maximum of NAD+ charge-transfer complexes.

“We have shown that NAD+ of concentration 1.03E-2M, when mixed with fairly strong electron donors, such as substituted pteridines, uric acid, serotonin creatine sulphate, lysergic acid, and phenothiazines, gave solutions which were coloured yellow to orange because of the formation of charge-transfer complexes." (A. Fulton, 1967)

Some of the electron donor molecules studied were LSD, indole, uric acid, promazine, and promethazine, and different absorption maximums were obtained for each donor-NAD+ complex as shown in Table 1 below. Also the researchers measured the ionization potential energies of the electron donors, and found that LSD had an ionization potential of 7.8 electron Volts, indole (7.9), uric acid (7.5), promazine (7.2), promethazine (7.2), and chlorpromazine (7.3).

From Hallucinogens HOMO, charge-transfer

The authors found that the absorption maximum of the charge-transfer complex correlated reasonably with the ionization potential of the electron donor drug, but not so well with the energies of the HOMO, perhaps because there are many approximations involved in the theoretical studies of the HOMO energy. However other groups have found a correlation between the absorption maximum and kHOMO energies.

As listed in Table 1 above, the LSD-NAD+ charge-transfer complex had an absorption maximum at 340 nm, which is the absorption maximum of the native LSD molecule. This compares to the 520 nm absorption maximum that is characteristic of LSD-TCNE or LSD-Ehrlich complexes.



References

Fulton A. and L. E. Lyons. (1967). Electron-accepting strength of NAD+. Aust.J.Chem. 20, 2267-2268.

LSD charge-transfer complexes 1. LSD-tetracyanoethylene

The electron donor molecule LSD forms a charge-transfer complex with the electron acceptor tetracyanoethylene (TCNE). The charge-transfer complex has a characteristic absorption band, allowing the detection of the presence of LSD. When LSD or other hallucinogen drugs are applied to a silica gel plate and then sprayed with either TCNE or electron acceptor drugs, a color band is detected.

In 1968, Millie and colleagues studied the electronic properties of methoxylated indoles and tryptamines by their ability to form charge-transfer complexes with TCNE or 1,3,5-trinitrobenzene (TNB), another electron acceptor. Many indoles and phenothiazines form a charge-transfer complex with TCNE or TNB; the wavelength of the absorption maximum of the complex is often between 300-720 nm. As shown in the figure below, the authors found a correlation between the absorption maximum of the acceptor-TCNE or acceptor-TNB complexes and kHOMO values of the electron donors (i.e. indoles or tryptamines). The y-axis is 1000/lambda, where lambda is the maximum absorption wavelength of the charge-transfer reaction product.

From Hallucinogens HOMO, charge-transfer

1-methyl-LSD was among the indoles and phenothiazines that were tested. The charge-transfer complex of TCNE and 1-methyl-LSD (letter p, Figure 1 above) had an absorption maximum at 520 nm. As determined by Huckel calculations, 1-methyl-LSD had kHOMO=0.487. This kHOMO value is slightly larger than Karreman's 1959 report of Ehomo=0.218 for LSD, suggesting slightly less electron donating ability. According to the figure above, the electron-donating ability of 1-methyl-LSD (p) lies between 4-methoxy-indole (i) and 5-methoxy-indole (k). I don't know why Millie and colleagues choose to study 1-methyl-LSD, which has one tenth the potency of LSD, instead of LSD.

TCNE-bezene complexes are used to study the electron-donating properties of different benzene derivatives

The ionization potential of an electron donor molecule can predict the rate of formation of its drug-TCNE complex. This was shown by Domelsmith in 1977. Several different benzene derivatives were mixed with the electron acceptor TCNE, and the rate of formation of benzene-TCNE complexes was measured. When the apparent enthalpy of formation of the benzene-TCNE complexes was plotted versus the average of the first and second ionization potential energies of the benzene molecules, as shown in Figure 12 below, an excellent linear correlation was obtained.

From Hallucinogens HOMO, charge-transfer

There is no mystery about the physical and chemical forces that bind a hallucinogen drug to biological receptors. The forces may be compared with the physical and chemical forces that bind TCNE to benzene or indoles. Charge-transfer forces predict the extent of drug binding to biological receptors, and the extent of behavior disarrangement produced by mescaline or LSD is correlated with the kHOMO, showing a direct role of charge-transfer forces on the extent of consciousness alteration.

Quantum mechanics is the method used to calculate the kHOMO energy. The dose of structurally diverse hallucinogens to produce consciousness alteration is correlated with the drug's kHOMO value, so it is very likely that quantum electronic properties of matter play a role in the mechanism of consciousness alteration.


References

Domelsmith, L. N., L.L. Munchausen and K.N. Houk (1977). Photoelectron spectra of psychotropic drugs. 1. phenethylamines, tryptamines, and LSD. J. Am. Chem. Soc. 99, 4311-4321.

Fulton A. and L. E. Lyons. (1967). Electron-accepting strength of NAD+. Aust. J. Chem. 20, 2267-2268.

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. 10.1021/jm00308a003