Steric and electronic relationships among some hallucinogenic compounds.

Stereochemical considerations and total valence electron calculations suggest congruities among the ostensibly dissimilar hallucinogenic compounds, D-lysergic acid diethylamide (LSD), indolcalkylamines, and methoxylated amphetamines. In LSD the aromatic benzene ring A and the N-6 nitrogen are essential for hallucinogenic activity; these sites may react with the receptor. The conformations of amphetamines and indolealkylamines at the receptor are such that the aromatic benzene ring lies like ring A of LSD and the alkylamino nitrogen lies like the N-6 of LSD. Ring A may interact with the receptor by forming a pi-molecular complex, as suggested by the correlation between hallucinogenic activity and energy of the highest occupied molecular orbital (E(H)) of congeneric series. The N-6 nitrogen of LSD and the sterically congruent nitrogen of the other hallucinogenic compounds may react with the receptor by forming a donor acceptor complex of the n-pi(*) or n-sigma(*) type. Other portions of the hallucinogenic molecules confer a favorable E(H): these include the methoxy and hydroxyl groups of the amphetamines (and mescaline), and the indolealkylamines; and the pyrrole ring of LSD and the indolealkylamines.