Further structure-activity studies on the lowering of brain 5-hydroxyindoles by 4-chloroamphetamine

Abstract

A single injection of 4-chloroamphetamine lowered brain 5-hydroxytryptamine (5-HT) in rats, with the maximum effect at 16 hr. Multiple injections were no more effective than a single injection, and 20–40% of the 5-HT in brain persisted. No other 4-substituted amphetamines studied lowered 5-HT as much as did 4-chloroamphetamine, though 5-hydroxyindoleacetic acid (5-HIAA) levels were decreased as much by 4-trifluoromethylamphetamine. The addition of a β-hydroxyl to 4-chloroamphetamine diminished the lowering of 5-HT despite the presence of the β-hydroxyl compound in brain at levels comparable to those of 4-chloroamphetamine. When metabolic inactivation by para-hydroxylation was not a factor (as in guinea pigs or in desmethylimipramine-treated rats), 3-chloro but not 2-chloroamphetamine lowered brain 5-HT as 4-chloroamphetamine did. 2-Chloroamphetamine in desmethylimipramine-treated rats was present in brain at levels comparable to those of 4-chloroamphetamine, but the 2-chloro compound raised instead of lowered 5-HT levels. Addition of a 2-chloro substituent to 4-chloroamphetamine reduced the effect on 5-HT, whereas the decrease in 5-HIAA was at least as great with 2,4-dichloroamphetamine as with 4-chloroamphetamine. The dichloro compound was present in brain at slightly lower levels than 4-chloroamphetamine and caused slightly less CNS stimulation and hyperthermia; both compounds were found primarily in the paniculate fraction after high speed centrifugation of brain homogenates. The ability of some 4-chloroamphetamine derivatives to lower 5-HIAA more than 5-HT suggests that inhibition of tryptophan hydroxylation cannot completely account for their effects on brain 5-hydroxyindole levels.