Behavioural Effects of some Derivatives of Amphetamine and LSD and their Significance

Summary

N,N-dimethyl derivatives of hallucinogenic amphetamines are far less potent than the parent compounds. In rats, 4-methoxyamphetamine produced a typical hallucinogenic profile at 3 mg/kg, but its N,N-dimethyl derivative was totally inactive at 25 mg/kg. Similarly, DOM (2,5-dimethoxy-4-methyl amphetamine) was active at 2.5 mg/kg, while its N,N-dimethyl derivative was inactive at 20 mg/kg. These results suggest that the amino group is necessary for activity and that these compounds likely bond using their nitrogen atoms. The activity of methoxylated amphetamines correlates more with quantum chemical properties, such as Hückel molecular orbital energies and native fluorescence, than with steric properties.

Study at a glance

Abstract

IN attempts to work out possible mechanisms of action of the hallucinogenic drugs, it would be helpful to know which chemical groups modify their activity. In the methoxylated amphetamines, some methoxy groups may act as electrostatic binding sites and some may effect the shape and energy distribution of the π cloud. It may also be important to know whether the amino group is necessary for activity. It has been shown that N,N-dimethylmescaline is a less potent compound than mescaline^1,2. We have now tested further N,N-dimethyl derivatives of hallucinogenic amphetamines using the Bovet-Gatti profiles on the Sidman avoidance schedule^3,4 which we have found to discriminate between hallucinogenie drugs very well. 4-Methoxyamphetamine is a very potent disrupting drug in rats and produces a typical “hallucinogenic” profile at 3 mg/kg (equivalent to mescaline at 25 mg/kg). The N,N-dimethyl derivative was totally inactive at 25 mg/kg. 2,5-Dimethoxy-4-methyl amphetamine (DOM) is the most potent human hallucinogenic amphetamine known (active in rats at 2.5 mg/kg). Its N,N-dimethyl derivative was also quite inactive at 20 mg/kg. These results suggest that, if these compounds bond, they do so using their N atoms, in which case our hypothesis^5 would predict that the 3-compound (not yet tested) would be an active hallucinogen. The relative activity of methoxylated amphetamines seems to correlate more with their quantum chemical properties, such as their Hückel molecular orbital (HMO) energies and degree of native fluorescence^6, than with their steric properties. That is to say, the steric requirements seem to be an unhindered N and an unhindered ortho or para methoxy group, and the energetic requirement is a high HMO energy.