Hallucinogenic receptor models: interaction of imidazolium chloride with amphetamine analogs

The interactions of several hallucinogenic phenethylamines with the biologically relevant electron acceptor imidazolium chloride have been investigated by monitoring phenethylamine 1H NMR chemical shift changes upon complex formation. Methoxy- and methylenedioxy-substituted phenethylamines interact with imidazolium chloride to form weak charge-transfer complexes that have a relatively narrow range of association constants. The results indicate the formation of a ternary complex in which a chloride ion is hydrogen bonded to a N+H side chain proton of the drug and a NH imidazolium proton. The imidazolium ring is positioned above a nonsubstituted ortho-position of the aromatic ring. Spectral assignment of the two diastereotopic benzylic protons allowed the geometry of the complex to be defined in more detail. Complexation occurs preferentially on that side of the phenethylamine molecule that allows the side chain alpha-methyl group to face away from the chloride ion and the imidazolium ring. The drug molecule exists in the complex in the preferred trans conformation. The biological relevance of this model is discussed.