Ziprasidone hydrochloride (CP-88059 hydrochloride) is a united 5-HT (serotonin) and dopamine receptor antagonist which shows potent effects of antipsychotic activity.

5-HT2A:0.42 nM (Ki), 5-HT1A receptor (human):2.5 nM (Ki), D2 receptor (rat):4.8 nM (Ki), 5-HT1A receptor (rat):3.4 nM (Ki)

Ziprasidone exhibits an inherent protective mechanism against drug-induced increases in food intake, demonstrated by its ability to inhibit the significant enhancement of food consumption caused by olanzapine in rats. It also induces a notable upregulation of NGF and ChAT immunoreactivity in the hippocampal regions dentate gyrus, CA1, and CA3 of rats. Furthermore, Ziprasidone dose-dependently decreases the activity of midbrain central tegmental field neurons (ED50 = 300 mg/kg i.v.), similar to atypical antipsychotics like clozapine (ED50 = 250 mg/kg i.v.) and olanzapine (ED50 = 1000 mg/kg i.v.) in anesthetized rats. In Xenopus oocytes, Ziprasidone displays a lower inhibitory effect (IC50 = 2.8 mM) on the wild-type hERG current.

Ziprasidone blocks wild-type hERG currents in a voltage and concentration-dependent manner with an IC(50) of 120 nM in stably transfected HEK-293 cells. Minimal hERG current blockade by ziprasidone is estimated during depolarized voltages (-20 or +30 mV) or assessed via envelope of tail test (+30 mV). The compound significantly prolongs the time constant of the slow component of hERG current deactivation at -50 mV. Ziprasidone acts as a 5-HT(1A) receptor agonist and antagonizes 5-HT(2A), 5-HT(2C), and 5-HT(1B/1D) receptors, similar to the antidepressant imipramine in inhibiting serotonin and norepinephrine neuronal uptake. It also exhibits high affinity for human 5-HT receptors and dopamine D(2) receptors.