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

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

Ziprasidone demonstrates the ability to inhibit the significant increase in food intake induced by olanzapine in rats, indicating an intrinsic protective mechanism against drug-induced hyperphagia. Furthermore, Ziprasidone significantly enhances the immunoreactivity of NGF and ChAT in the dentate gyrus, CA1, and CA3 regions of the rat hippocampus. In anesthetized rats, Ziprasidone exhibits a dose-dependent reduction in the activity of midline thalamic neurons, similar to atypical antipsychotic drugs such as clozapine (ED50 = 250 mg/kg i.v.) and olanzapine (ED50 = 1000 mg/kg i.v.), with an ED50 value of 300 mg/kg i.v. Additionally, Ziprasidone has a relatively low blocking effect on the wild-type hERG current in Xenopus oocytes, with an IC50 of 2.8 mM.

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