Psychedelic drugs: steric factors that predict psychotropic activity.

Psychedelic drugs are a class of compounds that produce a characteristic set of profound and unique changes in human perception, thought, and feeling. There are at least three structurally dissimilar classes of psychedelic drugs: the lysergic acid group, derivatives of tryptamine, and compounds related to phenylethylamine or phenylisopropylamine. Within each of these structural classes, some compounds are potent psychedelic agents while others are ineffective. Several workers have attempted to find chemical or biological properties that are unique to active psychedelic agents of differing chemical structure. Effective psychedelic drugs that have been examined elevate brain concentrations of serotonin,I and central sympathetic stimulation parallels psychedelic potency.2 It is probable that these compounds act on the same central receptor, since cross tolerance occurs between psychedelic drugs of such diverse structures as d-lysergic acid diethylamide (LSD), psilocybin, and mescaline.3' 4 We observed a close relationship between the potency of psychedelic drugs and their electronic configurations5 A theoretical model was developed that predicted the potency of psychedelic agents within a given structural class on the basis of the energy of their highest occupied molecular orbital. Recently, in making molecular models (Dreiding-stereo models [Swissco]) of a variety of psychedelic compounds of tryptamine, phenylethylamine, and phenylisopropylamine classes, we observed that they could all approximate a unique conformation, simulating in part rings A, B, and C of LSD (Fig. 1). This report describes the conformation of a variety of psychedelic molecules,