Synthesis and pharmacological examination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA).
The racemate and the enantiomers of 1-(3-methoxy-4-methyphenyl)-2- aminopropane (6) and racemic 5-methoxy-6-methyl-2-aminoindan (11) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Both 6 and 11 were found to substitute with high potency in 3,4-(methylenedioxy)methamphetamine (1) and (S)-1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (2) trained rats. In the latter assay, both enantiomers of 6 had identical potencies, but their dose-response curves were not parallel. Racemic 6, but not 11, partially substituted for LSD. Racemic 6 and 11 did not substitute in (S)-amphetamine-trained rats. All of the test compounds were potent inhibitors of [3H]-5-HT uptake into synaptosomes in vitro, with the S enantiomer of 6 being most active. Rat brain monoamine levels were unaltered 1 week following a single high dose (10 or 20 mg/kg, sc) of 6 or 11, or two weeks following a subacute dosing regimen (20 mg/kg, sc, twice a day for 4 days). In addition, radioligand-binding parameters in rat brain homogenate with the 5-HT uptake inhibitor [3H]paroxetine were unchanged after subacute dosing with either racemic 6 or 11. The results indicate that compounds 6 and 11 have animal behavioral pharmacology similar to the methylenedioxy compounds 1 and 2, but that they do not induce the serotonin neurotoxicity that has been observed for the latter two drugs.
Johnson
M P
MP
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
Frescas
S P
SP
Oberlender
R
R
Nichols
D E
DE
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D007189:Indans / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007189:Indans; D010627:Phenethylamines; D012702:Serotonin Antagonists; C068879:5-methoxy-6-methyl-2-aminoindan; D015104:3,4-Methylenedioxyamphetamine; C068878:1-(3-methoxy-4-methylphenyl)-2-aminopropane; D018817:N-Methyl-3,4-methylenedioxyamphetamine