“The model here arises from a reduction of variables until the molecule in the isolated state remains as the governing structure dictating the magnitude of observable phenomena. The extraction of structure-activity relationships from this model leads to information which is necessarily limited by certain exclusions of reality, but which is frequently the most attainable kind of relationship.” (Kier L.B., 1978)Domelsmith studied the ionization potentials of LSD, tryptamines, and amphetamines. The ionization potential was significantly correlated with the quantities of drug needed to displace LSD binding from rat brain membranes (-log ED50). Out of 5 drugs plotted here, LSD is the most potent binder to rat brain membranes, and the best electron donor with average ionization potential energy=7.65 eV. This plot includes mescaline (5), DMT (4), and LSD (1), regarded as structurally different types of hallucinogens.
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| From Domelsmith ionization potential |
There are many dissimilarities in chemical structure between LSD (1), chlorpromazine (2), promethazine (3), DMT (4), and mescaline (5), yet there is a trend toward better electron-donating ability with the more planar and rigid drugs.
In another series of correlations, the average of the first and second ionization potential energies was plotted versus Vogel's minimum effective brain level (MEBL), a measure of hallucinogen activity in rats. Out of 10 drugs, LSD (1) had the lowest ionization potential and the highest biological potency (MEBL).
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| From Domelsmith ionization potential |
The next figure shows the same plot, with labels beside each data point. The unsubstituted compounds phenethylamine (PA) and amphetamine (A) are the least potent psychotomimetics and have the largest ionization potential energies (~9 eV), while LSD and 5-methoxy-tryptamine (5MT) are the most potent in terms of MEBL and have the smallest ionization potential energies (~7.5 eV). Note that plain tryptamine plus MAO inhibition (T) is plotted and represents one of the most potent drugs in terms of IP and MEBL.
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| From Domelsmith ionization potential |
The electron-donating ability of the LSD molecule itself deserves special attention. It is thought that the productive binding of a drug to its receptor is responsible for the primary biological response, but embodied within this index of receptor binding are other relationships more directly related, as Domelsmith's research shows. A correlation between drug potency in humans and 5-HT2 receptor affinity may in fact reflect the drug's HOMO energy.
References
Kier, L. B. (1971). In Molecular orbital theory in drug research, De Stevens, G., Ed., Medicinal chemistry, Academic press: New York, Vol. 10.
Domelsmith L. N., L. L. Munchausen and K. N. Houk. (1977). Lysergic acid diethylamide. Photoelectron ionization potentials as indices of behavioral activity. J. Med. Chem. 20, 1346-1348.
