Interactions that define the alkylamine side-chain conformation in phenylalkylamine hallucinogens: an ab initio study

Different interactions that define the alkylamino side chain conformation i n phenylalkylamine hallucinogen compounds are studied with HF/6-31G* ab ini tio calculations and natural bond orbital, NBO, analyses. These studies wer e performed on three model compounds, namely, 2,3,4-trimethoxyphenethylamin e (IM) I, 3,4,5-trimethoxy-phenethyl-amine (mescaline), II, and 2-methyl-2, 5-dimethoxy-amphe-tamine (DOM) III. It was found that the three of them pre sent three alkylamino rotamers which can be classified as gauche-1, gauche- 2 and trans according to the C-NH2 orientation with respect to the C-alpha- C-beta bond. Although in all cases the ganche-1 conformer is the preferenti al one, its relative stability with respect to the trans one was found to d ecrease when increasing the hallucinogen potency. A variety of interactions could be identified and their role played in that behavior are discussed. (C) 2000 Elsevier Science B.V. All rights reserved.