IN THE SEARCH FOR A NOVEL CLASS OF ANTIPSYCHOTIC-DRUGS - PRECLINICAL PHARMACOLOGY OF FG5803, A 1-PIPERAZINECARBOXAMIDE DERIVATIVE

Comparative studies of the 1-piperazinecarboxamide derivative nzoyl)pr opyl]-N-cyclohexyl-1-piperazinecarboxamide hydrochloride (FG5803) were made with clozapine and haloperidol. Receptor studies revealed that F G5803 potently and selectively bound to the serotonin type 2A receptor s (K-I = 13 nM). FG5803 inhibited and hydroxytrytophan- and 2,5-dimeth oxy-4-iodophenyl)-2-aminopropane-induced head twitches, which indicate d potent in vivo serotonin type 2A receptor antagonism. FG5803 caused an acute activation of the tuberoinfundibular dopamine neurons and pro duced only a transient rise in plasma prolactin. In behavioral studies in rats, FG5803 showed strong antagonistic action on presynaptic dopa minergic autoreceptors but only weak postsynaptic dopamine D-2 blockad e. FG5803 was not cataleptogenic and did not antagonize amphetamine-in duced stereotypies. FG5803 was active in the reduction of aggressive b ehavior and spontaneous exploratory behavior in mice and rats. Therefo re, FG5803 is expected to constitute a promising approach in the searc h for a novel class of antipsychotic drugs that have a broader spectru m of activity and fewer adverse effects than the conventional, antidop aminergic antipsychotics.