Studies of four novel diphenylbutylpiperazinepyridyl derivatives on release and inhibition of reuptake of dopamine, serotonin and noradrenaline by rat brain in vitro.

Four novel diphenylbutylpiperazinepyridyl derivatives (FG5865 (2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-3-pyridine- carboxamide), FG5891 (2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-N-methyl-3- pyridinecarboxamide), FG5893 (2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-3- pyridinecarboxylic acid methyl ester) and FG5909 (2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-3-hydroxypyridine) were tested concerning their effects on in vitro release and reuptake of neurotransmitters. Serotonin, noradrenaline and dopamine were those considered, with rat synaptosomes prepared respectively from frontal cortex, cortex and striatum. FG5865, FG5891, FG5893 and FG5909 were found to potently inhibit the uptake of all three neurotransmitters. In addition, FG5865, FG5891 and FG5893 increased the release of serotonin and dopamine from perfused frontal cortical and striatal tissue; FG5865 was most potent in this regard. The release induced by the FG compounds was, however, much less than that induced by e.g. fenfluramine or amphetamine. All four FG compounds were also found to inhibit glutamate-stimulated release of dopamine from striatal tissue; for FG5893 this inhibition occurred at nanomolar concentrations.