Wednesday, April 26, 2017

2-position of LSD

The carbon skeleton of indole is represented by a pentagon and hexagon fused together. The nitrogen, on the pentagon section, is the only nitrogen in the molecule. Typical naming in organic chemistry treats this nitrogen as number 1, thus the 2-position of indole refers to the second atom from it. If indole or 5-HT is superimposed on the LSD molecule, its 2-position is analogous to the 2-position of LSD, making it easy to compare the three molecules.

The 2-position of LSD has the highest free valence, suggesting that this site may be involved in electron donation in charge-transfer complexes (Kier, 1971). Likewise, the 2-position of 5-HT has been identified as having a high frontier electron density. In discussions of HOMO and LUMO values of different molecules, Snyder wrote,
"As with all the tryptamine derivatives examined, the region of the highest frontier electron density in LSD is at the #2 carbon atom." (Snyder,S.H. 1965)
In the formation of a charge-transfer complex, electron acceptor molecules interact with specific sites of the indole ring, rather than with the pi electron system as a whole. For example in the formation of serotonin-picrate crystals, the nitro groups of picric acid were found to interact with C-2 and C-3 of 5-HT (Bugg and Thewalt, 1970). Thus, there are some striking features about Carbon-2 and Carbon-3 whether in 5-HT or LSD.

Snyder continued,
"If a charge transfer mechanism is involved in the hallucinogenic action of LSD, the #2 carbon should be critical for this activity. It is, therefore, interesting to note that 2-Brom-LSD and 2-oxy-LSD, which contain sterically obstructing substituents at the #2 carbon, are devoid of hallucinogenic effect, even though they readily enter the brain." (Snyder,S.H. 1965)
According to Snyder, the reason for greatly diminished or no psychelic effects in the 2-brom derivative of LSD (BOL-148) is because the bromine atom obstructs the reactive site. Alternately, a bromine at position-2 could alter the electronic properties of the molecule as a whole, so that it is less likely to interact with the biological receptor. In terms of its outer shell configuration, bromine brings at least 3 sets of paired electrons in its p-orbitals. Adding these sets of paired electrons could weaken the pi cloud.  A similar situation may happen with oxygen in 2-oxy-LSD although it has 2 sets of paired electrons. 

It has been noted that lifting the 2,3-double bond in LSD weakens drug potency considerably (Keup, 1970). This would suggest that a change in the electronic properties, and not necessarily steric bulk, is what accounts for diminished potency of BOL-148.

MLD-41 differs from LSD by 1 methyl group on Nitrogen 1. It is just 10X less potent than LSD, so it is not like BOL-148 which is much less potent or 2-oxy-LSD which is said to be biologically inactive. The Carbon in the methyl group would have no pairs of electrons in its outer shells; its outer shell electrons are involved with C-C and C-H bonding. Could it affect the nearby pi clouds? The methyl group on the Nitrogen is small, so it seems unlikely that steric bulk would keep it from interfacing well with the receptor. 

It has also been reported, by Kumbar and Sankar, that there is a significant frontier electron density present on carbon 8 of LSD (Kumbar and Sankar, 1973).


Reference

Snyder S. H. and C. R. Merril (1965). A relationship between the hallucinogenic activity of drugs and their electronic configuration. Proceedings of the Natational Academy of Sciences U. S. A. 54, 258-266.


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

Keup W. 1970. Structure-activity relationship among hallucinogenic agents; In Origin and mechanisms of hallucinations. Proceedings of the 14th annual meeting of the Eastern Psychiatric Research Association held in New York City, November 14-15, 1969, W. Keup (Ed.), Plenum Press, New York, pp. 345-376.

Kier L. B. Molecular orbital theory in drug research. New York, Academic Press, 1971.

Kumbar M. and D. V. Sankar (1973). Quantum chemical studies on drug actions. 3. correlation of hallucinogenic and anti-serotonin activity of lysergic acid derivatives with quantum chemical data. Research communications in chemical pathology and pharmacology 6, 65-100.