INTERACTION OF THE NOVEL ANTIPSYCHOTIC DRUG AMPEROZIDE AND ITS METABOLITE FG5620 WITH CENTRAL-NERVOUS-SYSTEM RECEPTORS AND MONOAMINE UPTAKESITES - RELATION TO BEHAVIORAL AND CLINICAL EFFECTS

Behavioral, biochemical, and electrophysiological studies suggest that amperozide affects mesolimbic and mesocortical dopamine neurotransmis sion. The receptor binding profile of amperozide is discussed and rela ted to behavioral and clinical, i.e., antipsychotic, effects of the dr ug. As previously reported, amperozide displayed high affinity for ser otonin 5-HT2A receptors (K-i = 16 nmol/L), and moderate affinity for s triatal dopamine D-2 (K-i = 540 nmol/L) and cortical alpha(1)-adrenerg ic receptors (K-i = 172 nmol/L). In the present study amperozide displ ayed low affinity for several serotonin receptor subtypes as well as f or the dopamine D-4 receptor transfected in COS7 cells (K-i D-4.2 = 76 9 nmol/L and K-i D-4.4 = 384 nmol/L). Amperozide was very weak or did not interact with several other receptor species including adrenergic, histaminergic, muscarinic, benzodiazepine, gamma-aminobutyric acid, a mino acid, opiate, and Ca channels; however, amperozide was found to c ompete for [H-3]paroxetine binding for the serotonin transporter in th e nanomolar range (K-i = 49 nmol/L). In vitro and in vivo binding pote ncy of amperozide correlates best with behavioral effects, indicating 5-HT2A antagonism, although serotonin uptake inhibition may contribute to the effects of amperozide on dopamine neurotransmission. The metab olite of amperozide, FG5620, displayed 5-10 times lower pharmacologic activity than amperozide. These properties of amperozide may suggest t hat the antipsychotic effects of amperozide are mediated by 5-HT2A rec eptors, although 5-HT uptake inhibition and alpha(1)-adrenergic recept or-mediated effects may be considered, particularly at higher doses. ( C) 1997 Society of Biological Psychiatry.