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-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.
Cozzi
N V
NV
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA.
Frescas
S
S
Marona-Lewicka
D
D
Huang
X
X
Nichols
D E
DE
D000818:Animals; D001067:Appetite Depressants / Q000138:chemical synthesis / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D005277:Fenfluramine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D066298:In Vitro Techniques; D007189:Indans / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D009642:Norfenfluramine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D017374:Paroxetine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D001067:Appetite Depressants; D007189:Indans; D014179:Neurotransmitter Uptake Inhibitors; D011954:Receptors, Dopamine; D009642:Norfenfluramine; D005277:Fenfluramine; D012701:Serotonin; D017374:Paroxetine