Pharmacological and toxicological effects of beta-3,4-methylenedioxyamphetamine isomers
Marquardt, G.M.; Distefano, V.; Ling, L.L.
Toxicology and Applied Pharmacology 45(3): 675-683
1978
ISSN/ISBN: 0041-008X PMID: 725923 Document Number: 132690
Racemic and (R)-methylenedioxyamphetamine (MDA) caused apparent hallucinogenic and amphetamine-like behavioral responses in mice. (S)-MDA never produced apparent hallucinogenic behavior but was more potent than either (.+-.)- or (R)-MDA in eliciting an amphetamine-like behavioral response. The LD50 values of (.+-.)-, (S)- and (R)-MDA were determined to see if the differential behavioral effects carried over to the toxicities of these drugs. (S)-MDA was the most toxic agent, (R)-MDA was the least toxic and (.+-.)-MDA was of intermediate toxicity. Some mice died 6-18 h after dosing. Pretreatment with SKF 525-A [2-(diethylamino)ethyl-2,2-diphenylvalerate hydrochloride] markedly enhanced the toxicity of (R)-MDA while protecting mice from the toxic effects of (.+-.)- and (S)-MDA. (R)-MDA metabolism to (R)-.alpha.-methyldopamine [(R)-.alpha.-MeDA] may represent a detoxification mechanism. (S)-.alpha.-methyldopamine formed from (.+-.)- or (S)-MDA possibly was responsible for at least some of the toxic effects observed. Racemic, (S)- and (R)-MDA caused an initial pressor response in the cat which diminished in amplitude upon repeated administration. This response was blocked by phenoxybenzamine and was greatly reduced by reserpine pretreatment. The MDA isomers also potentiated the rise in blood pressure resulting from norepinephrine. (.+-.)-, (S) and (R)-MDA may produce initial pressor responses by an amphetamine-like action. (S)- MDA effects were indistinguishable from those of amphetamine. Repeated administration of (.+-.)- and (R)-MDA resulted in a depressor response after 4 or 5 treatments. This non-amphetamine-like effect was postulated to be mediated in part by (R)-.alpha.-MeDA formed as a metabolite of (.+-.)- and (R)-MDA in vivo. Low doses of (R)-.alpha.-MeDA produced a fall in blood pressure while higher doses and all doses of (S)-.alpha.-MeDA increased blood pressure by directly stimulating .alpha. receptors.