Comparison Of 4-Chloro-, 4-Bromo- And 4-Fluoroamphetamine In Rats (Copyright R. W. Fuller, J. C. Baker, K. W. Perry And B. B. M~Lloy)

Newophormacology.

1975, 14. 739-746. Pergamon Press. Printed in Gt. Brrtain.

COMPARISON OF 4-CHLORO-, 4-BROMO- AND 4-FLUOROAMPHETAMINE IN RATS: DRUG LEVELS IN BRAIN AND EFFECTS ON BRAIN SEROTONIN METABOLISM
R. W. FULLER, J. C. BAKER, K. W. PERRY and B. B. M~LLOY
The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46206
(Accepted 3 March 1975)

Summary-Theability of 4-chjo~oamphetamine, 4-bromoamphetamine, and 4-fluoroamphetamine to deplete brain S-hydroxyindoles and some pharmacokinetic properties of these drugs were compared in rats. Half-lives of the three compounds in rat brain were 3.7, 4.4, and 5.7 hr, respectively for the 4-fluoro, 4-chloro, and 4-bromo amphetamines. The tendency of the drugs to be associated with particulate material in brainhomogenates or to prefer an organic versus an aqueous phase in uitro varied in the order 4-bromo > 4-chloro > 4-fluoro. This order of activity also applied to the inhibition of monoamine oxidase in vitro. All three 4-haloamphetamines reduced the activity of tryptophan hydroxyiase and lowered the levels of serotonin and S-hydroxyindoleacetic acid in whole brain initially. With ~chloroamphe~mine and4-bromoamphetamine, the depletion of brain 5-hydroxyindoies lasted for at least a week. 4-F~uoroamphetamine, in contrast, lowered serotonin and 5-hydroxyindolea~tic acid levels only for short times (2-6 hr) after drug injection, and 5-hydroxyindole levels were essentially back to normal within 24 hr. Prior treatment with an uptake inhibitor prevented the serotonin depletion by all of thehaloamphetamines, indicating they all required the membrane uptake pump for entry into the neurone. The effect of 4-bromoamphetamine, like that of 4-chloroamphetamine, could be reversed by subsequent injection of the uptake inhibitor after short periods but not after 2448 hr. The failure of 4-tluoroamphetamine to produce a long-lasting depletion of brain serotonin like that produced by 4chloroamphetamineor 4-bromoamphetamine may reflect the inability of the fluoro-compound to be metabolized in the same way as the other haloamphetamines.

p-Chloroamphetamine has been one of the most widely used drugs for influencing brain serotonin levels. We have previously studied a number of derivatives of p-chloroamphetamine to define the structural requirements for affecting serotonin metabolism and topartially dissociate the multiple actions that p-chloroamphetamine seems to exert (FULLER, HINES and MILLS, 1965; FULLER and MOLLOY, 1974; FULLER, PERRY, WONG and MOLLOY, 1974; FULLER, SNODDY, ROUSH and MOLLOY, 1973). The structural modifications previously made have included changing the position of the chlorine on the ring, varying the length of the side chain, hydroxylating the ring or side chain,and modifying the amine function to yield possible metabolites of 4-chloroamphetamine. In this communication, we report comparative studies of three different haloamphetamines having chlorine, bromine, or fluorine substituted in the 4 position of the aromatic ring. 4-Bromomethamphetamine has been shown to lower brain serotonin levels (KNOLL and MAGYAR, 1971; LEONARD and SHALLICE, 1971; LEONARD,1972), but a comparison of 4-bromoamphetamine and 4-chloroamphetamine has not been reported. One particularly interesting feature of the action of 4-chloroamphetamine is its remarkably long duration and the transition from a reversible to an irreversible effect (SANDERS-BUSH, RUSHING and SULSER, 1972a; FULLER and SNODDY, 1974; FULLER, PERRY and MOLLOY, 1974). These aspects have not been studied with4-bromoamphetamine up to this time. Virtually no information on the 4-fluoro-compound has been available. In this paper we report that these derivatives, like 4-chloroamphetamine, affect brain serotonin but that the nature of their effects and of their biological disposition differs in some respects from the 4-chloro-compound.
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R. W. FULLER, C. BAKER, W. PERRY B. B. MOLLOI .I. K....