Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential

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.