Impact of Functional Group Modifications on Designer Phenethylamine Induced Hyperthermia

The popularity of designer phenethylamines such as synthetic cathinones (bath saltS) has led to increased reports, of life-threatening hyperthermia. The diversity of chemical modifications has resulted in the toxicological profile of most, synthetic cathinones being mostly uncharacterized. Here, we investigated the thermogenic effects of six recently identified designer phenethylamines (4-1-nethylinethamphetamine, methylorte, mephedrone, butylone, pentylone, and MDPV) and compared these effects to the established thermogenic agent 3,4-methylenedioxymethainphetamine (MDMA). Specifically, we determined the impact of alpha,beta-ketone, alpha-alkyl, or pyrrolidine functional group on core body temperature changes. Sprague Dawley rats(n = 5-6) were administered a dose (30 mg/kg, sc) of a designer phenethylamine or MDMA, and core body, temperature measurements were recorded at 30 thin intervals for 150 min post treatment. MDMA elicited the greatest maximum temperattire change (Delta T-max.), and this effect was significantly greater than that of its beta-ketone analogue, methylone.Temperature area under the curves (TAUCs) and Delta T-max were also significantly different between 4-methylinetharriphetamine (4-MMA) and its beta-ketone analogue mephedrone. Lengthening the alpha-alkyl chain of methylone to produce butylone and pentylone significantly attenuated the thermogenic response on both TAUCs and Delta T-max, compared to those of methylone; however, butylone and pentylone were not different from each other. Pyrrolidine Substitution on the N-terminus of pentylone produces 3,4-methylenedioxypyrovalerone1 (MDPV), which did not significantly alter core body temperature: Thermogenic comparisons MDMA vs methylone and 4-MMA vs mephedrone indicate that oxidation,at the benzylic position significantly attenuates the hyperthermic response. Furthermore, either extending the alpha-alkyl chain to ethyl and propyl (butylone and pentylone, respectively) or extending the alpha-alkyl chain arid adding a pyrrolidine on the N-terminus (MDPV) significantly blunted the thermogenic effects of methylone. Overall, the present study provides the first structure activity relationship in vivo, toxicological analysis of designer phenethylamines.