The abuse of psychomotor stimulants such as the synthetic cathinones (typically referred to as designer drugs or bath salts) is a continuing and very serious problem worldwide for which there is no accepted medication. Among these compounds are 3,4-methylenedioxypyrovalerone (MDPV) and alpha-pyrrolidinovalerophenone (APV). Both of these stimulants act as a norepinephrine-dopamine reuptake inhibitors and can cause hyperstimulation, paranoia, hallucinations and heart failure. The latter is also known as flakka and $5 insanity and has been implicated in causing bizzare violently aggressive behavior in some individuals. We have pursued the chemical synthesis and identification of biogenic amine agonists and their antagonists as research tools and potential medications. In one example, we developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is enabling numerous studies requiring this critical research tool. We have also studied the discriminative stimulus effects of MDL100,907 and several other drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. Illicit racemic MDPV manufactured in clandestine labs is racemic and we hypothesized that most of the activity resides in one of the enantiomers of the racemate. In order to obtain a sufficient amount of the enantiomers of rac-MDPV to determine their activity, we improved the known synthesis of rac-MDPV and found chemical resolving agents, (+)- and (-)-2'-bromotetranilic acid, that gave the MDPV enantiomers in >98% enantiomeric purity as determined by (1) H nuclear magnetic resonance and chiral high-performance liquid chromatography. The absolute stereochemistry of these enantiomers was determined by single-crystal X-ray diffraction studies. We have studied racemic MDPV and the S-(+)- and the R-(-)-enantiomers in the mouse. Mice were trained to discriminate 10 mg/kg cocaine from saline, and substitutions with racemic MDPV, S(+)-MDPV, and R(-)-MDPV were performed. Mice reliably discriminated the cocaine training dose from saline, and each form of MDPV fully substituted for cocaine, although marked potency differences were observed such that S(+)-MDPV was most potent, racemic MDPV was less potent than the S(+) enantiomer, and R(-)-MDPV was least potent. At both ambient temperatures, locomotor stimulant effects were observed after doses of S(+)-MDPV and racemic MDPV, but R(-)-MDPV did not elicit locomotor stimulant effects at any tested dose. These studies suggest that all three forms of MDPV induce biologic effects, but R(-)-MDPV is less potent than S(+)-MDPV and racemic MDPV. Taken together, these data suggest that the S(+)-MDPV enantiomer is likely responsible for the majority of the biologic effects of the racemate and should be targeted in therapeutic efforts against MDPV overdose and abuse.
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