Fenfluramine

Pemoline [2152-34-3] (24), stmcturally dissimilar to amphetamine or methylphenidate, appears to share the CNS-stimulating properties. As a consequence, pemoline is employed in the treatment of ADHD and of narcolepsy. There are several other compounds that are stmcturally related to amphetamines, although not as potent and, presumably, without as much abuse potential. These compounds also have anorexic effects and are used to treat obesity. Some of the compounds available are phentermine [122-09-8] fenfluramine [458-24-2] and an agent that is available over-the-counter, phenylpropanolamine [1483815-4] (26). 

A study was conducted to measure the concentration of D-fenfluramine HCl (desired product) and L-fenfluramine HCl (enantiomeric impurity) in the final pharmaceutical product, in the possible presence of its isomeric variants (57). Sensitivity, stabiUty, and specificity were enhanced by derivatizing the analyte with 3,5-dinitrophenylisocyanate using a Pirkle chiral recognition approach. Analysis of the caUbration curve data and quaUty assurance samples showed an overall assay precision of 1.78 and 2.52%, for D-fenfluramine HCl and L-fenfluramine, with an overall intra-assay precision of 4.75 and 3.67%, respectively. The minimum quantitation limit was 50 ng/mL, having a minimum signal-to-noise ratio of 10, with relative standard deviations of 2.39 and 3.62% for D-fenfluramine and L-fenfluramine. 

Fenclofenac 37 Fenclorac 66 Fenclozic acid 269 Fendosal Fenestrel 9 Fenethylline U 425 Fenfluramine 1, 70 Fenimide 2T7 Fenisorex 391... 

C2H4O 75-07-0) see L-Alanine cz.v-Cefprozil Chloral hydrate Fencamfamin Fenfluramine Fluroxene ... 

C21H22F3N3OS 807-57-8) see Fluphenazine Y-[4-(trifluoromethyl)phenoxyJbenzenepropanamine -(Ci HiftFjNO 83891-03-6) see Fluoxetine (3-trifluoromethylphenyl)acetone (CioHgFjO 21906-39-8) see Fenfluramine (3-trifluoromethylphenyl)acetone oxime (CiijHkjFjNO, 834-19-5) see Fenfluramine [[[2-(trifiuoromethyl)phenyl]amino]methylene]propane-dioic acid diethyl ester (C 3Hi(,F3N04 23779-94-4) see Floctafenine... 

Fatten CK, Ziedonis D, Clare AW, et al D-Fenfluramine-induced prolactin responses in postwithdrawal alcoholics and controls. Alcohol Clin Exp Res 19 1578-1582, 1995... 

Finally, the actions of the so-called 5-HT releasing agent , if-fenfluramine, which is well known for its anorectic effects, should be mentioned here. This compound inhibits 5-HT uptake but its metabolite, if-norfenfluramine, increases 5-HT release as do high doses of (i-amphetamine. It is important to realise that this 5-HT release is independent of nerve impulses and the action of such compounds rests on their effects on the 5-HT transporters on the storage vesicles and terminal membrane. Once these drugs have been taken up into 5-HT neurons by the transporter, they cause 5-HT to leak out of its storage vesicles and, ultimately, to be extruded from the neuron by retrotransport (see below and Chapter 4 for further details). 

A link between 5-HT transmission and hypophagia is further reinforced by the pharmacology of drugs that reduce food intake ( anorectic agents), such as (7-fenfluramine or sibutramine. Both these compounds have actions that should lead to increased synaptic concentrations of 5-HT in the brain, albeit through different mechanisms (see below), but whether or not this actually explains the anorectic actions of (7-fenfluramine is controversial. 

An important distinction between the effects of sibutramine and i/-fenfluramine is highlighted by microdialysis studies (Heal et al. 1998). These show that the rate of increase in 5-HT efflux in the region of the PVN, after administration of sibutramine, is slow, progressive and long-lasting. This is because it relies on the accumulation of extracellular 5-HT following the inhibition of its reuptake after impulse-dependent release. This time-course contrasts with the rapid and transient increase in 5-HT efflux which results from the fenfluramine type of impulse-independent release from nerve terminals. In fact, this rapid increase in 5-HT release is thought to underlie the serious adverse side-effects of (i-fenfluramine that have led to its withdrawal from the clinic. 

A final, important distinction between sibutramine and (7-fenfluramine is that the actions of the former, but not the latter, rest on its modification of both 5-HT and noradrenergic transmission. Thus, the reduction in food intake by sibutramine is partially blocked by ai- or jSi-adrenoceptor antagonists as well as 5-HT2a/2C or 5-HT2b/2c antagonists. In fact, there appears to be a synergistic interaction between these two transmitter systems. This is illustrated by a study of the effects of the selective serotonin... 

In view of the apparent pleasurable effects of MDMA, it becomes of considerable interest to understand the mechanism of action of substances with a similar effect. Major efforts have been directed toward the study of agents that have an effect on serotonin pathways, since that is the neurotransmitter system that seems most implicated in the mechanism of action of MDMA. This hypothesis is further reinforced by the observation that MDMA substitutes for fenfluramine (Schechter 1986). and fenfluramine substitutes for MBDB (Oberlender and Nichols, unpublished). The substitution data for (+)-amphetamine and cocaine in (-t-)-MBDB-trained rats are also similar to the data for substitution of these agents in fenfluramine-trained rats (White and Appel 1981). 

While MDMA produces CNS stimulation and euphoria, fenfluramine is more of a sedative and dysphoric. A detailed comparison of the pharmacology of fenfluramine and MDMA may be necessary to understand exactly how MDMA works. 

One might also speculate that PCA would have an effect similar to MDMA. Indeed, the early clinical data for PCA suggested that it possessed antidepressant activity (Verster and Van Praag 1970). This would suggest that the human psychopharmacology of PCA may well be closer to that of MDMA than fenfluramine, but it is unlikely that clinical studies can be carried out to study this. 

My second question is this You mentioned ferrfluramine. I presume you used the racemic mixture, which would mean that in the brain you would have both R and S fenfluramine and R and S norfenfluramine present. And since these differ widely in their effects on dopamine versus serotonin neuronal systems, have you studied individual enantiomers of either fenfluramine or norfenfluramine ... 

ANSWER Actually we used synthesized (-l-)-fenfluramine. The fluoxetine story is not clear. It does not block the discriminative cue, but other workers have shown that it blocks the neurotoxicity. We have not looked at it in enough detail or at any of the in vitro models to see whether it blocks or releases serotonin. 

White, F.J., and Appel, J.B. A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine. Psychopharmacology (Berlin) 73 110-115, 1981. 

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