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Cathinone: An Investigation of Several N-Alkyl and Methylenedioxy-Substituted Analogs

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Abstract

DAL CASON, T. A., R. YOUNG AND R. A. GLENNON. Cathinone: An investigation of several N-alkyl and methylenedioxy-substituted analogs. PHARMACOL BIOCHEM BEHAV 58(4) 1109–1116, 1997.—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.

Section snippets

Drug Discrimination Studies

Nine male Sprague–Dawley rats (ca. 250–300 g), housed individually, were reduced in body weight to approximately 80% of their free-feeding weight. During the entire course of the study, the animals’ body weights were maintained at this level by partial food deprivation; in their home cages, the animals were allowed drinking water ad lib. The animals were trained (15-min training session) to discriminate intraperitoneal injections (15-min presession injection interval) of 1.0 mg/kg of

Results

N-Monoethylcathinone (N-Et CAT; ED50 = 0.77 mg/kg), N-mono-n-propylcathinone (N-Pr CAT; ED50 = 2.03 mg/kg), racemic N,N-dimethylcathinone and its (−)-isomer [(±)Di Me CAT, ED50 = 0.61 mg/kg; (−)Di Me CAT, ED50 = 0.44 mg/kg], and (+)N,N-dimethylamphetamine [(+)Di Me AMPH; ED50 = 2.92 mg/kg] all resulted in stimulus generalization when administered to (+)amphetamine-trained animals (ED50 = 0.33 mg/kg) (Table 1). In some cases [N-Pr CAT, (+)Di Me AMPH)], the animals’ response rates were decreased

Discussion

As appears to be the case with amphetamine 9, 34, 36, 37, N-monomethylation of cathinone results (at least) in retention of potency [19], but any further increase in alkyl chain length results in a progressive decrease in potency (Table 1). The ED50 values for racemic cathinone, its N-methyl (i.e., methcathinone), N-ethyl (i.e., N-Et CAT), and N-n-propyl (i.e., N-Pr CAT) derivatives are 0.71, 0.37, 0.77, and 2.03 mg/kg) (see Table 3). These results, then, are not unexpected and represent

Acknowledgements

This work was supported, in part, by NIH Grant DA-01642. We would like to thank Dr. M. Gabryszuk for his assistance with some of the stimulus generalization studies.

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