3,4-Methylenedioxymethamphetamine (MDMA): Stereoselective interactions at brain 5-HT₁ and 5-HT₂ receptors

Abstract

3,4-Methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxy-amphetamine (MDA), and their optical isomers, were assayed for their affinities at radiolabeled brain serotonin (5-HT₁, 5-HT₂) and dopamine (D₂) binding sites. (R(−)-MDA and R(−)-MDMA) displayed moderate affinities for ³H-ketanserin-labeled 5-HT₂ sites (Ki=3425 and 3310 nM, respectively) whereas the affinities for their S(+)-enantiomers were lower (Ki=13,000 and 15,800 nM, respectively). Similar absolute and relative affinities were obtained at ³H-serotonin-labeled 5-HT₁ sites; binding at D₂ sites was very low (Ki>25,000 nM in each case). The (−)>(+) order of potency at 5-HT₂ sites is consistent with the observation that R(−)-MDA is a more potent psychoactive agent than its S(+)-enantiomer, but contrasts with the reported finding that S(+)-MDMA is more potent than R(−)-MDMA in humans. These results suggest that MDMA, unlike MDA and other hallucinogenic phenylisopropylamines, does not work primarily through a direct interaction at 5-HT sites.