The serotonin (5-HT) receptor affinities and behavioral (discriminative stimulus) properties of a series of 4-substituted derivatives of 1-(2,5-dimethoxyphenyl)-2-aminopropanes (2,5-DMA) were investigated. The substituents at the 4-position included H, OMe, OEt, Me, Et, F, Br, I, and NO2. Substituent lipophilicities (pi values) of these functionalities appear to have a minimal effect on either 5-HT receptor affinity or behavioral activity. Those derivatives previously found to be most potent in human studies possess significant affinity for 5-HT receptors. Furthermore, when rats trained to discriminate (+/-)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline were used, generalization was found to occur upon administration of the 4-substituted 2,5-DMA derivatives. Because a direct relationship exists between the ED50 values obtained from these discrimination studies and human hallucinogenic potencies, the discriminative stimulus paradigm, with DOM as a training drug, appears to be a useful tool for comparing the quantitative and qualitative (DOM-like) effects produced by certain hallucinogenic agents.

The enantiomers of a series of methoxy-and alkyl-substituted phenylisopropylamines were prepared by low-pressure reduction of imines formed by reaction of the appropriate phenylacetones with either (+)or (-)-a-methylbenzylamine, followed by hydrogenolysis of the hydrochlorides of the resulting-/V-(a-phenethyl)phenylisopropylamines. Values of [a]D are reported and enantiomeric purities were, in the range 96-99%. Overall yields ranged from 30 to 60%. Glc or fluorine nmr analysis of enantiomeric purity was accomplished using a-methoxy-a-trifluoromethylphenylacetamides. Glc analysis of the jV-trifluoroacetyl-S-prolylarnides was used to confirm R-(-) and S-{+) absolute configurations of all compounds. (+)or (-)-2,5-dimethoxyamphetamine was brominated to give the (+)or (-)-4-bromo compound. The enantiomers of 1,2,3,4-tetrahydro-2-naphthylamine could not be prepared by this method.Generally, optical isomers of a drug molecule possess differing degrees of biological activity. In the case of amphetamine, norepinephrine uptake into synaptosomes from noradrenergic regions of the brain is inhibited to a greater degree by the 5-(+) than by the R-(-) enantiomer.2'3 In addition, the two isomers of amphetamine are not equally good substrates for side-chain metabolizing enzymes in certain animal species.4 Since Gordis5 has found that no racemization of either isomer occurs when amphetamine is administered to man, it is possible that the complex effects of psychotomimetic amphetamines could be partially due to the fact that racemic mixtures have been used for testing.In the report by Barfknecht and Nichols® on the effects of (i?)-(-)-and (S)-(+)-3,4-dimethoxyamphetamine (3, in the rat, it was suggested that LSD could be considered as a phenethylamine derivative. Natural lysergic acid 1 possesses the 5R,8R absolute configuration7'8 and it was predicted that the psychotomimetic effects of the amphetamines might reside in the R enantiomers, based on their stereochemical relationship to lysergic acid. This prediction is consistent with stereochemical correlations between LSD, phenethylamines, and tryptamines proposed by Kang and Green.9 Indeed, it was found that the R-(-) isomer of 3,4-DMA seemed to be responsible for the psychotomimetic effects in the rat.6

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