The effects of stereoisomers of 2-amino-6(7)- and 9-amino-6-trifluoromethylbenzonorbornenes on food intake, brain serotonin concentration, and monoamine oxidase activity.
To evaluate the importance of the conformation of fenfluramine in eliciting its various central nervous system effects, the isomers of 2-amino-6(7)- and 9-amino-6-trifluoromethylbenzonorbornene were employed as conformationally defined analogs of norfenfluramine. In this series of isomeric amines, the exo-2 and anti-9 isomers resemble the fully extended conformation of fenfluramine, whereas the endo-2 and syn-9 isomers resemble the folded conformation. The exo-2 and anti-9 isomers were equi-effective in reducing food intake in the rat, but were approximately seven times less potent than fenfluramine. The endo-2 and syn-9 isomers had no effect on food intake up to a dose of 40 mg/kg. All of the isomers were as effective as amphetamine in inhibiting brain monamine oxidase type B. These isomers also inhibited monoamine oxidase type A to the same extent as type B, but were significantly less potent than amphetamine in inhibiting this form of the enzyme. The effects at anorectic doses on brain serotonin (5-HT) concentration were also studied. Although fenfluramine decreased brain 5-HT concentration, the exo-2, syn-9 and anti-9 isomers had no significant effect. The endo-2 isomers caused an 11% decrease in 5-HT concentration, but this effect was observed at higher doses of the compound. The data suggest that the fully extended conformation of fenfluramine is preferred over the folded conformation for eliciting its anorectic activity. However, no conclusion can be made for the conformational requirements for the other biological responses investigated in this study.
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects*; D005277:Fenfluramine / Q000494:pharmacology*; D008297:Male; D008968:Molecular Conformation; D008996:Monoamine Oxidase Inhibitors; D009636:Norbornanes / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D009636:Norbornanes; D005277:Fenfluramine; D012701:Serotonin; C041087:2-amino-6-trifluoromethylbenzonorbornene; C041088:9-amino-6-trifluoromethylbenzonorbornene; D000661:Amphetamine