A re-examination of the mono-methoxy positional ring isomers of amphetamine, methamphetamine and phenyl-2-propanone.

Recently, tablets inscribed with the Mitsubishi 3-diamond logo, and sold as 3,4-methylenedioxymethamphetamine (MDMA), were found to contain p-methoxymethamphetamine (PMMA), a compound with MDMA-like effects. Shortly after this first submission, similarly inscribed tablets were encountered containing both PMMA and p-methoxyamphetamine (PMA). This second tablet composition has been implicated in several recent deaths in the US. Because two other positions are available for mono-methoxy substitution on the phenyl ring, it is essential that the correct identification be made for these compounds. Analytical data are supplied to enable differentiation of these ring isomers as well as the ketones that serve as their precursors.

Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs.

Structurally, methcathinone is to cathinone what methamphetamine is to amphetamine. Due to increased interest in the abuse of such agents we wished to determine if certain derivatives of cathinone would behave in a manner consistent with what is known about their amphetamine counterparts; that is, can amphetamine structure-activity relationships be extrapolated to cathinone analogs? As expected on the basis of known structure-activity relationships for amphetaminergic agents, both N-monoethylcathinone and N-mono-n-propylcathinone (N-Et CAT and N-Pr CAT; ED50 = 0.77 and 2.03 mg/kg, respectively) produced amphetamine-like stimulus effects in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle and were somewhat less potent than racemic methcathinone. In contrast, (-)N,N-dimethylcathinone or (-)Di Me CAT (ED50 = 0.44 mg/kg) was more potent than expected; although (+)N,N-dimethylamphetamine is sevenfold less potent than (+)methamphetamine, (-)Di Me CAT is only about 1.6-fold less potent than (-)methcathinone, and is essentially equipotent with (-)cathinone. In addition, although it has been previously demonstrated that 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) results in stimulus generalization in rats trained to discriminate (+)amphetamine or DOM from vehicle, the cathinone counterpart of MDA (i.e., MDC) resulted in partial (maximum: 58%) generalization in (+)amphetamine-trained animals, and failed to produce >7% DOM-appropriate responding in rats trained to discriminate DOM from vehicle. On the other hand, the N-methyl analog of MDC (i.e., MDMC) behaved in a manner similar to that of the N-methyl analog of MDA (i.e., MDMA); that is, a (+)amphetamine stimulus (MDMC: ED50 = 2.36 mg/kg) but not a DOM stimulus generalized to MDMC. In MDMA-trained rats, stimulus generalization occured both to MDC and MDMC (ED50 = 1.64 and 1.60 mg/kg, respectively). Although this and previous studies have demonstrated that significant parallelisms exist between the structure-activity relationships of amphetamine analogs and cathinone analogs, we now report several unexpected qualitative and/or quantitative differences. It is suggested that caution be used in attempting to draw conclusions or make predictions about the activity and potency of novel cathinone analogs by analogy to the structure-activity relationships derived from amphetamine-related agents; it would appear that each new cathinone analog will require individual investigation.

Neurotoxic and pharmacologic studies on enantiomers of the N-methylated analog of cathinone (methcathinone): a new drug of abuse.

These studies evaluated neurotoxic and pharmacologic properties of the R(+) and S(-) enantiomers of methcathinone, a psychostimulant drug that has surfaced in the illicit drug market, primarily in the S(-) form. Neurotoxic potential toward brain dopamine (DA) and serotonin (5-HT) neurons was assessed by measuring DA and 5-HT axonal markers and by means of silver degeneration studies; pharmacologic effects were evaluated by measuring locomotor stimulation. Methcathinone produced dose-related neurotoxic and locomotor stimulant effects which were species- and enantiomer-dependent. In mice, although both enantiomers produced toxic effects on DA neurons, the R(+) enantiomer was more potent, and neither enantiomer produced long-term effects on 5-HT neurons. By contrast, in behavioral studies, both enantiomers increased mouse locomotor activity, but the S(-) enantiomer was more potent, which suggests that methcathinone's neurotoxic and locomotor stimulant effects may be separable. Additional studies were done with rats, because mice are often refractory to 5-HT neurotoxicity induced by amphetamines. In the rat, both enantiomers produced toxic effects on DA neurons, only S(-)-methcathinone produced toxic effects on 5-HT neurons, and both enantiomers produced comparable locomotor stimulant effects. Together, these results indicate that: 1) Methcathinone has the potential to damage DA and 5-HT neurons; 2) Methcathinone neurotoxicity is enantiomer and species dependent; 3) Methcathinone's neurotoxic and locomotor stimulant effects are dissociable in mice but not rats; and 4) N-methylation confers 5-HT toxic activity onto cathinone, the N-desmethyl derivative of methcathinone, which is known to lack 5-HT neurotoxic activity.

Methcathione ("cat"): an enantiomeric potency comparison.

With regard to its chemical structure, methcathinone is to cathinone what methamphetamine is to amphetamine. Although it is a drug of abuse outside the United States, methcathione is only recently making an appearance on the clandestine market in this country and has just been classified a Schedule I substance under the Emergency Scheduling Act. We have previously demonstrated that racemic methcathinone produces locomotor stimulation in mice, and substitutes for cocaine and (+)amphetamine in rats trained to discriminate either cocaine or (+)amphetamine, respectively, from saline in tests of stimulus generalization. Because an enantiomeric potency comparison has never been reported for the optical isomers of methcathinone, in the present investigation we synthesized samples of S(-)- and R(+)methcathinone and compared them for their ability: a) to produce locomotor stimulation in mice, b) to elicit cocaine-like responding in rats trained to discriminate 8.0 mg/kg of cocaine from saline vehicle, and c) to elicit (+)-amphetamine-appropriate responding in rats trained to discriminate 1.0 mg/kg of (+)amphetamine from saline vehicle. S(-)Methcathinone was about twice as potent as S(+)amphetamine and three to five times more potent than R(+)methcathinone in the three pharmacologic assays. We conclude that both optical isomers possess central stimulant character, but that S(-)methcathinone is somewhat more potent than R(+)methcathinone.

Chiral resolution of cationic drugs of forensic interest by capillary electrophoresis with mixtures of neutral and anionic cyclodextrins.

Chiral resolution of a number of cationic drugs of forensic interest (amphetamine, methamphetamine, cathinone, methcathinone, cathine, cocaine, propoxyphene, and various alpha-hydroxyphenethylamines) is achieved via capillary electrophoresis (CE) with added cyclodextrins (CDs), including novel mixtures of neutral and anionic CDs. In the latter studies, resolution and migration speed are readily adjusted by varying the ratio of the two added CDs, as the anionic CD acts as a counter-migrating complexing reagent. The neutral CD, heptakis(2,6-di-O-methyl)-beta-CD, was found suitable for the analysis of illicit cocaine and khat leaves (Catha edulis Forsk), which contain (-)-alpha-aminopropiophenone ((-)-cathinone), (+)-norpseudoephedrine (cathine), (-)-norephedrine, and trace levels of the phenylpentenylamines (+)-merucathinone, (+)-merucathine, and possibly (-)-pseudomerucathine. The use of mixtures of the neutral and the anionic CD (beta-CD sulfobutyl ether IV) was found suitable for the analysis of illicit amphetamine, methamphetamine, methcathinone, and propoxyphene. A model is presented for the impact of mixtures of neutral and anionic CDs on migration behavior and chiral resolution in CE.