John Sprague of Bowling Green State University, Ohio will present Impact of functional group modifications to designer phenethylamines and opioids on the legal and functional effects of drugs of abuse at the Biochemistry Biannual Seminar.
The Biochemistry Biannual Seminar is a special seminar series highlighting work at the intersection of Chemistry and Biology.
Monday, November 5th 5:00 pm in CNS 333
Pizza and Beverages Provided
Clandestine laboratories alter the chemical structure of different synthetic cathinones (bath salts) to produce new agents they hope will generate a greater feeling of euphoria or circumvent existing laws. Ohio implemented the “pharmacophore rule” in an attempt stay ahead of these clandestine laboratories. This rule has recently been extended to the synthetic opioids. Here, we will review the fundamentals of the pharmacophore rule as they apply to synthetic cathinones and opioids. Additionally, research examining the pharmacodynamics (PD) and pharmacokinetics (PK) effects of the common chemical modifications made to 3,4-methylenedioxymethamphetamine (MDMA, Molly) to generate the bath salts has revealed differences in PD and PK measures. We investigated the thermogenic effects of six recently identified designer phenethylamines (4-methylmethamphetamine, methylone, mephedrone, butylone, pentylone, and MDPV) and compared these effects to MDMA. Specifically, we determined the impact of a β-ketone, α-alkyl, or pyrrolidine functional group on body temperature changes. Thermogenic comparisons of MDMA vs methylone and 4-MMA vs mephedrone indicate that oxidation at the benzylic position significantly attenuates the hyperthermic response. Furthermore, either extending the α-alkyl chain to ethyl and propyl (butylone and pentylone, respectively) or extending the α-alkyl chain and adding a pyrrolidine on the N-terminus (MDPV) significantly blunted the thermogenic effects of methylone. The non-selective α1 and β adrenergic receptor antagonist carvedilol was also able to reverse established hyperthermia mediated by MDMA, methylone and mephedrone. Further, we investigated the in vivo plasma and CNS PK of three synthetic cathinones whose structures differ by lengthening of the α-alkyl chain: methylone (-CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3). The plasma PK values are consistent with the greater lipophilicity associated with α-alkyl side chain lengthening. Conversely, in the CNS, methylone and butylone displayed higher Cmax and AUC0-∞ values than pentylone. These contrary findings in the CNS and plasma demonstrate that lengthening of the α-alkyl chain of methylone, butylone, and pentylone yields differential PK properties in the CNS as compared to the plasma. These findings demonstrate that although all these agents share a common phenethylamine pharmacophore, chemical modification to the pharmacophore scaffold can alter the drugs PK and PD response.
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