Effect of 1-(3,4-methylenedioxyphenyl)-2-aminopropane and its optical isomers in PMMA-trained rats

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

“…Keeping these caveats in mind, it is nevertheless interesting to note that our results are consistent with the possibility that activation of TAAR1 contributes to amphetamine-like effects. In particular, our data show ( S )- 3 to be twice as potent as ( R )- 3 at both rh TAAR1 and h TAAR1, and ( R )- 4 to be inactive at h TAAR1 while ( S )- 4 retained weak activity, consistent with the observation that for MDA ( 3 ) and MDMA ( 4 ) the ( S )- isomers, but not the ( R )-isomers, substitute for ( S )-amphetamine in drug discrimination studies in rats 2, 35 and with the notion that psychomotor stimulant activity is associated with the ( S )-configuration of these agents. 36 In humans doses of 100 mg (or greater) of ( S )- 3 or ( S )- 4 , but not of ( R )- 3 or ( R )- 4 , have been reported to lead to excitation.…”

“…While we did not collect quantitative data on N-norfenfluramine ( 6 ), the fact that only ( S)- 6 was found to be active at h TAAR1 is consistent with the finding that ( S)- 6 was more potent than ( R )-6 in counteracting amphetamine induced increase in locomotor activity in rats. 41 While this effect is likely to be associated with activation of 5-HT 2 activation, it does not preclude involvement of TAAR1.…”

“…2 The DOM-like (hallucinogenic) effect has been associated with activation of the 5-HT 2 family of receptors. 3–5 In fact, the binding potencies of hallucinogenic amphetamines such as DOM, DOB, DOEt at 5HT 2A/C receptors have been shown to correlate with measures of hallucinogenic potencies in rodent and the ( R )–enantiomer has been found to possess higher potency than the ( S )- enantiomer, 6 consistent with binding data at 5-HT 2A/C receptors.…”

Designer drugs: a medicinal chemistry perspective

“…7). The prototypical compounds for the three classes were the central stimulant (+)‐amphetamine (( S )‐B4), the LSD‐like agent 2,5‐dimethoxy‐4‐methylamphetamine (DOM, B5), and, p‐methoxymethamphetamine (PMMA, B6), 36 which apparently elicits MDMA‐like responses in humans 37 …”

“…Generalization studies in rodents have led to classification of commonly abused drugs into three overlapping groups as illustrated in Figure 7. Thus, amphetamine (B4) and methamphetamine (B8) generalize only to (+)‐amphetamine (( S )‐B4) (group S); DOM (B5), DOEt (B10), and DOB (B11) generalize to racemic DOM (B5) (group H) and not to (+)‐amphetamine (( S )‐B4) 40 or PMMA (B6); 35 drugs like 3,4‐DMA (B12) and MBDB (B13) 41 generalize only to PMMA (B6) (group O); racemic MDA (B14) generalizes to all three categories (group 4); 36 and racemic MDMA (B1) generalizes to (+)‐amphetamine (( S )‐B4) and to PMMA (B6) (group 2), but not to DOM (B5) 35 . Academic studies to determine the optimal conformation to elicit LSD‐like effects identified constrained analogs of the compounds in class H with potencies in rodents exceeding that of LSD (B7) 42 .…”