Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential

Nicholas V. Cozzi, Stewart Frescas, Danuta Marona-Lewicka, Xuemei Huang, David E. Nichols

Research output: Contribution to journalArticle

13 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)709-715
Number of pages7
JournalPharmacology Biochemistry and Behavior
Volume59
Issue number3
DOIs
StatePublished - Mar 1 1998

Fingerprint

Norfenfluramine
Fenfluramine
Serotonin
Pharmaceutical Preparations
indan
2-aminoindan
Rats
Assays
Body Weight
Pharmacology
Appetite Depressants
Paroxetine
Cyclization
Serotonin Uptake Inhibitors
Amphetamine

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

Cite this

Cozzi, Nicholas V. ; Frescas, Stewart ; Marona-Lewicka, Danuta ; Huang, Xuemei ; Nichols, David E. / Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential. In: Pharmacology Biochemistry and Behavior. 1998 ; Vol. 59, No. 3. pp. 709-715.
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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-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.",
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Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential. / Cozzi, Nicholas V.; Frescas, Stewart; Marona-Lewicka, Danuta; Huang, Xuemei; Nichols, David E.

In: Pharmacology Biochemistry and Behavior, Vol. 59, No. 3, 01.03.1998, p. 709-715.

Research output: Contribution to journalArticle

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T1 - Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential

AU - Cozzi, Nicholas V.

AU - Frescas, Stewart

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