Effect of the R(-) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors.
J F Nash, B L Roth, J D Brodkin, D E Nichols, Gary A. Gudelsky
Neuroscience Letters August 1, 1994 DOI: 10.1016/0304-3940(94)90057-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro pharmacological study Peer reviewed |
|---|---|
| Population | Cultured cells expressing either 5-HT2A or 5-HT2C receptors |
| Measures | [3H]inositol monophosphate accumulation |
| Topics | MDMA Serotonin |
| Keywords | Cells, cultured 3t3 cells Fibroblasts Animals Mice N-methyl-3,4-methylenedioxyamphetamine Phosphatidylinositols Receptors, serotonin Receptor, serotonin, 5-ht2a Receptor, serotonin, 5-ht2c Structure-activity relationship Hydrolysis Stereoisomerism |
| Key points | MDA and MDMA isomers act as weak agonists at 5-HT2A and 5-HT2C receptors, with stereoselective differences: R(-)MDA is more potent than S(+)MDA at 5-HT2A, while at 5-HT2C the MDA isomers are equipotent and S(+)MDMA is more efficacious than R(-)MDMA. All compounds had affinities 2-3 orders of magnitude lower than serotonin. The authors propose this intrinsic activity may contribute to neurotoxicity at high doses. |
Abstract
The effect of the R(-) and S(+) isomers of 3,4-methylenedioxyamphetamine (MDA) and its N-methyl analog 3,4-methylenedioxymethamphetamine (MDMA) on [3H]inositol monophosphate accumulation was studied in cells expressing either 5-HT2A or 5-HT2C receptors. The isomers of MDA produced a concentration dependent increase in phosphatidyl inositol (PI) hydrolysis at the 5-HT2A receptors, with the R(-) isomer of MDA being more potent than the S(+) at the 5-HT2A receptor. The R(-) and S(+) isomers of MDMA were significantly less efficacious at the 5-HT2A receptor as compared to MDA; S(+)MDMA had no effect. At the 5-HT2C receptor, both R(-) and S(+)MDA were equipotent at stimulating PI hydrolysis, with the S(+) isomer of MDMA being more efficacious at the 5-HT2C receptor compared with the R(-) isomer. In all cases at both the 5-HT2A and 5-HT2C receptors, the affinities of the isomers of MDMA and MDA were at least 2-3 orders of magnitude less than 5-HT. Despite the weak effect of these compounds at the 5-HT2A and 5-HT2C receptors, these substituted amphetamines do possess intrinsic activity which may contribute to their neurotoxic effects when administered at high doses.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
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- 5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine European Journal of Pharmacology November 1, 1992
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