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

Abstract

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)].

Keywords:

• Phenylethylamine
• amphetamine
• monomethylated phenylethylamines
• para-monohalogenated phenylethylamines
• acute toxicity mice
• mice LDLO
• LD50
• LD100

Acknowledgments

The authors thank the late Professor E.A. Zeller for his invaluable input to this work. They greatly appreciate the skillful technical assistance of Dr. S. Huprikar and Mr. S. Myles. This research was supported, in part, by The National Migraine Foundation, Chicago, IL.

Disclosure statement

The authors declare that they have no conflict of interest related to this research.