N-Methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) and N-Methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) produce non-identical discriminative stimuli in rats

Abstract

N-Methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (methylenedioxymethamphetamine, MDMA, Ecstasy) and its structurally abbreviated congener N-methyl-1-(4-methoxyphenyl)-2-aminopropane (para-methoxymethamphetamine, PMMA) are chemically related designer drugs, and PMMA is sometimes sold on the clandestine market as a substitute for MDMA. Prior drug discrimination studies have found that MDMA and PMMA substitute for one another suggesting that they produce similar discriminative stimulus effects in rats. However, there also are some indications that the two agents produce distinct stimulus effects. In this study, further comparisons were made between the stimulus effects of these two agents. Sprague-Dawley rats were trained to discriminate either 1.25 mg/kg of PMMA or 1.5 mg/kg of MDMA from saline vehicle in a two-lever operant paradigm. A structure-activity comparison revealed that MDMA and PMMA behave similarly upon homologation of their terminal amine substituents. In contrast, the PMMA stimulus, unlike an MDMA stimulus, failed to generalize completely to the psychostimulant cocaine, 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OH DPAT), and R(-)-1-(3-methoxyphenyl)-2-aminopropane [R(-)MMA]. In an additional group of animals, a (+)amphetamine stimulus partially generalized to R(-)MMA. Taken together, the results argue and re-emphasize the conclusion that the stimulus effects produced by MDMA and PMMA are similar, but non-identical, and that PMMA is the less "stimulant-like" of the two.

Using Ca2+-channel biosensors to profile amphetamines and cathinones at monoamine transporters: electro-engineering cells to detect potential new psychoactive substances

“…In drug discrimination studies, MDMA showed generalization in PMMA-trained rats and partial generalization in S(+)amphetamine-trained rats, but is not recognized by DOM-trained rats. This suggests that MDMA is primarily an empathogen with some stimulant-like effects, but it is not a hallucinogenic agent (Glennon 1991;Glennon et al 2007;Oberlender and Nichols 1988). These observations correlate well with subjective effects previously described in humans, where MDMA was reported as a distinctive entity from hallucinogens and "pure" stimulants (O berlender and Nichols 1988).…”

Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class

“…Drug discrimination studies in rats showed racemic m -methoxyamphetamine ( 5 ) to produce amphetamine-like effect and to generalize to ( S )- 1 38 but not to DOM ( 8 ); examination of the individual enantiomers of 5 in drug discrimination studies showed significantly reduced response rates and disruption of behavior by both enantiomers. 39 Relatively high potency at h TAAR1 has also been found for ( S )- 2,5-dimethoxy-4-ethylamphetamine (( S )- 9 ), again suggesting that it may produce amphetaminelike effects. The literature data for racemic ( S )- 9 imply some anxiogenic effects in humans at low dose (25 mg); 37 but no clear-cut amphetamine-like stimuli of either of the individual enantiomers or of the racemate were detected in a study in which human subjects were given oral doses of 1–4 mg of 9 .…”

Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances

“…The amphetamine-derivatives MBDB, 4-MA, MDEA, 4-MTA, PMA, and PMMA show uptake inhibition profiles and DAT/SERT ratios similar to MDMA (Table 1). In vivo drug discrimination experiments in rats suggest that PMA, PMMA and 4-MTA show MDMAlike properties (Dukat et al 2002;Glennon et al 2007). However, these substances did not substitute for amphetamine in the drug discrimination experiments, which predicts that PMA, PMMA and 4-MTA have less stimulant-like properties than MDMA.…”