Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class.

The alpha-ethyl phenethylamine derivative 1-(1,3-benzodioxol-5-yl)-2-butanamine was prepared. An asymmetric synthesis was used to prepare the enantiomers of this compound and the related alpha-methyl homologue (MDA). The racemates and enantiomers of both compounds were evaluated in the two-lever drug discrimination assay in rats trained to discriminate saline from 0.08 mg/kg of LSD tartrate. Stimulus generalization occurred with the racemate and the R-(-) enantiomer of the alpha-methyl homologue and the S-(+) enantiomer of the alpha-ethyl primary amine. No generalization occurred with the other enantiomers or with the N-methyl derivatives of either series. Human psychopharmacology studies revealed that the N-methyl derivative of the title compound was nonhallucinogenic and that it had a new, novel psychoactive effect. It is suggested that this compound is the prototype of a new pharmacologic class that may have value in facilitating psychotherapy and that this class be designated as entactogens.

Synthesis and evaluation of 2,3-dihydrobenzofuran analogues of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane: drug discrimination studies in rats.

Two analogues, 6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran and 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran, of the hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were synthesized and tested in the two-lever drug discrimination paradigm. In rats trained to discriminate saline from LSD tartrate (0.08 mg/kg), stimulus generalization occurred to both of the 2,3-dihydrobenzofuran analogues but at doses more than 10-fold higher than for DOM. A possible explanation for this dramatic attenuation of LSD-like activity could involve a highly directional electrophilic binding site on the receptor that cannot accept the orientation of the unshared electron pairs on the heterocyclic oxygen atom in the benzofurans.

Unreliability of the rat stomach fundus as a predictor of hallucinogenic activity in substituted phenethylamines.

A series of three isomeric 2,4,5-substituted monoethoxy dimethoxy phenylisopropylamines were compared for their contractile effect in the rat fundus as potential antagonists to the effect of serotonin in the fundus. The three isomers were also evaluated for their discriminative stimulus properties in rats that had been trained to discriminate injections of saline from LSD tartrate (0.08 mg/kg). The drug discrimination studies revealed that the 2,5-dimethoxy-4-ethoxy substitution was most potent in rats, consistent with the reported clinical activity of this isomer in man. By contrast, of the three isomers examined, this was the weakest in eliciting a contraction in the fundus. None of the compounds antagonized serotonin induced contractions, and it was not possible to determine pA2 values. Questions are raised about the determination of pA2 values for partial agonists and it is concluded that the fundus is not a reliable model for prediction of hallucinogenic activity of phenethylamines.

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogues of hallucinogenic phenethylamines: lack of LSD-like biological activity.

cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine were synthesized as conformationally restricted analogues of hallucinogenic phenylisopropylamines. In rats trained to discriminate saline from LSD (0.08 mg/kg, ip) in a two-lever drug discrimination paradigm, no generalization of the LSD stimulus to the cis trimethoxy compound occurred at doses up to 20 mg/kg. For both of the trans compounds, partial generalization of the LSD cue occurred at doses of 5 mg/kg or greater. In contrast, complete generalization occurred with trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. The ED50 for this compound and the doses of the trans cyclobutyl homologues at which significant drug-appropriate responding occurred indicate that the latter are on the order of 50-75 times less potent than the cyclopropylamine analogue. The lack of generalization to the cyclobutylamines indicates either that their discriminative stimulus properties differ from LSD or that they lack discriminative effects.

Substituent branching in phenethylamine-type hallucinogens: a comparison of 1-[2,5-dimethoxy-4-(2-butyl)phenyl]-2-aminopropane and 1-[2,5-dimethoxy-4-(2-methylpropyl)phenyl]-2-aminopropane.

Two novel hallucinogen analogues related to 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, STP) were synthesized and evaluated in the two-lever drug discrimination paradigm by using 0.08 mg/kg of LSD as the training drug stimulus. The two compounds differ from each other only with respect to the point of branching in the 4-alkyl group. However, pharmacological evaluation revealed a clear difference in difference in potency and degree of LSD generalization for the two isomers. Branching adjacent to the ring, as in the 4-(2-butyl) analogue, may provide steric interference to the formation of the drug-receptor complex, while branching one methylene unit removed from the ring, as in the 4-(2-methylpropyl) analogue, poses less of a steric problem for the drug-receptor interaction. This is consistent with the idea that formation of a charge-transfer complex between the hallucinogen molecule and the receptor may be one of the features of this drug-receptor interaction.