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.
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.
Nash
J F
JF
Department of Psychiatry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-5000.
Roth
B L
BL
Brodkin
J D
JD
Nichols
D E
DE
Gudelsky
G A
GA
D015104:3,4-Methylenedioxyamphetamine / Q000494:pharmacology*; D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis / Q000187:drug effects; D051379:Mice; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010716:Phosphatidylinositols; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D015104:3,4-Methylenedioxyamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine