N-Ethyl-5-trifluoromethyl-2-aminoindan (ETAI) and 5-trifluoromethyl-2- aminoindan (TAI) were synthesized to examine the effects of side-chain cyclization on the pharmacology of the anorectic drugs fenfluramine (FEN) and norfenfluramine (norFEN), respectively. ETAI and TAI inhibited synaptosomal accumulation of 5-HT but were less effective at inhibiting catecholamine uptake than FEN or norFEN, respectively. In vivo, ETAI and TAI were less neurotoxic than FEN or norFEN; decreases in the number of [3H]paroxetine- labeled 5-HT uptake sites were 50% less than the decreases produced by FEN or norFEN. Rats treated with ETAI, TAI, FEN, and norFEN lost 10-15% of their pretreatment body weight over a 4-day period, while saline-treated control animals gained 8%. In two-lever drug discrimination (DD) assays in rats, TAI fully substituted for the 5-HT releaser/uptake inhibitor, (+)-MBDB [(+)-N- methyl-l-(1,3-benzodioxol-5-yl)-2-aminobutane]. ETAI produced only partial substitution in this test. Neither TAI nor ETA[ mimicked (+)-amphetamine in the DD assay. These studies demonstrate that incorporation of the side-chain of phenylisopropylamines into the five-membered ring of a 2-aminoindan changes both the molecular pharmacology and the neurotoxic profile of FEN and norFEN, but does not diminish the drugs' ability to reduce body weight.
All Science Journal Classification (ASJC) codes
- Clinical Biochemistry
- Biological Psychiatry
- Behavioral Neuroscience