Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential.

Abstract

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-1-(1,3-benzodioxol-5-yl)-2-aminobutane]. ETAI produced only partial substitution in this test. Neither TAI nor ETAI 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.

• Authors: N V Cozzi, S Frescas, D Marona-Lewicka, X Huang, D E Nichols
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 59 Issue 3 Pg. 709-15 (Mar 1998) ISSN: 0091-3057 [Print] United States
• PMID: 9512076 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Appetite Depressants
• Indans
• Neurotransmitter Uptake Inhibitors
• Receptors, Dopamine
• Norfenfluramine
• Fenfluramine
• Serotonin
• Paroxetine

Topics

• Animals
• Appetite Depressants (chemical synthesis, pharmacology)
• Body Weight (drug effects)
• Brain Chemistry (drug effects)
• Discrimination, Psychological (drug effects)
• Fenfluramine (analogs & derivatives, chemistry, toxicity)
• In Vitro Techniques
• Indans (chemistry, toxicity)
• Male
• Nervous System Diseases (chemically induced, physiopathology)
• Neurotransmitter Uptake Inhibitors (chemical synthesis, metabolism, pharmacology)
• Norfenfluramine (analogs & derivatives, chemistry, toxicity)
• Paroxetine (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Dopamine (drug effects)
• Serotonin (metabolism)
• Synaptosomes (drug effects, metabolism)