β-Phenylethylamine and various monomethylated and para-halogenated analogs. Acute toxicity studies in mice

Phenylethylamine's acute toxic effects in a population of adult (10 to 12 weeks old; ∼30 g) Swiss male albino mice are significantly increased by para-position aromatic ring halogenation. LD_LO, LD₅₀, and LD₁₀₀ values (mg/kg; x ± SEM) for p-F- (116.7 ± 3.3, 136.7 ± 1.7, and 160.0 ± 2.9), p-Br- (126.7 ± 3.3, 145.0 ± 2.9, and 163.3 ± 3.3), p-Cl- (133.3 ± 3.3, 146.7 ± 1.7, and 165.0 ± 2.9), and p-I-PEA (133.3 ± 3.3, 153.3 ± 1.7, and 168.3 ± 1.7), compared to PEA 203.3 ± 3.3, 226.7 ± 4.4, and 258.3 ± 8.8). Like PEA, the difference between LD_LO and LD₅₀, and LD₅₀ and LD₁₀₀ for individual amines were similar and in the range (10 to 20%). Toxicity variation between the various p-halogenatedPEAs also fell within a relatively narrow range (as a group: LD_LO 116.7 ± 3.3 to 133.3 ± 3.3, LD₅₀ 136.7 ± 1.7 to 153.3 ± 1.7, and LD₁₀₀ 160.0 ± 2.9 to 168.3 ± 1.7 mg/kg). PEA methylation, (exception of its α-methyl derivative), results in relatively modest changes in acute toxicity. LD_LO, LD₅₀, and LD₁₀₀ values (mg/kg; x ± SEM) for N-Me- (176.6 ± 3.3, 200.0 ± 2.9, and 221.7 ± 3.3), p-Me- (183.3 ± 3.3, 206.7 ± 3.3, and 225.0 ± 2.9), o-Me- (210.0 ± 5.8, 233.3 ± 3.3, and 258.3 ± 1.7), and β-MePEA (220.0 ± 5.8, 243.3 ± 4.4, and 278.3 ± 44). Similar to PEA, and the p-HPEAs, the difference between LD_LO and LD₅₀ and LD₅₀ and LD₁₀₀ values for individual amines fell within a relatively narrow range (10 to 20%). Variation in toxicity among the methylatedPEAs also fell within a limited range (as a group: LD_LO 176 ± 3.3 to 220 ± 5.8, LD₅₀ 200.0 ± 2.9 to 243.3 ± 4.4 and LD₁₀₀ 221.7 ± 3.3 to 278.3 ± 4.4 mg/kg). With the exception of PEA's methyl derivative (amphetamine) all the amines studied are rapidly metabolized by monoamine oxidase. This pharmacokinetics difference would help to explain the markedly higher amphetamine toxicity [(LD_LO, LD₅₀ and LD₁₀₀ (mg/kg; x ± SEM) of 21.3 ± 0.9, 25.0 ± 0.6, and 29.3 ± 0.7, respectively)].