Blockade of drug-induced deficits in prepulse inhibition of acoustic startle by ziprasidone.

Ziprasidone, an antipsychotic with efficacy against core symptoms of schizophrenia and schizoaffective disorder, has a low incidence of extrapyramidal syndrome (EPS). Because of its high 5-HT(2A)/D(2) binding-affinity ratio and low EPS liability, ziprasidone is considered to belong to the newer class of "novel" antipsychotics typified by clozapine. Its unique pharmacological profile, however, distinguishes it from other novel agents. We evaluated ziprasidone in the prepulse inhibition (PPI) model, which is sensitive to clinically active antipsychotics. Male Wistar rats were tested in acoustic startle sessions in which some startle-eliciting stimuli were presented alone, and others were preceded by a weak prepulse. Administration of the dopamine agonist apomorphine (1 mg/kg) or the N-methyl-D-aspartate (NMDA) antagonist ketamine (10 mg/kg) significantly disrupted PPI. When coadministered with either of these compounds, clozapine (1-5.6 mg/kg sc) and ziprasidone (5.6-17.8 mg/kg po) significantly attenuated the declines in PPI. Haloperidol (0.03-0.56 mg/kg) also attenuated drug-induced deficits in PPI but to a lesser extent (and at higher doses) with ketamine than with apomorphine. Together, these data confirm that ziprasidone shares common effects in PPI models with other novel antipsychotics. Ziprasidone's affinity for non-D(2) receptors in the central nervous system may partly account for its attenuation of ketamine's effect.

The discovery of potent and selective dopamine D4 receptor antagonists.

The identification of a novel dopamine receptor subtype, referred to as the D4 receptor, which binds the atypical antipsychotic drug clozapine with high potency, has led to the initiation of a drug discovery program that aims to find novel inhibitors of this receptor subtype. A selective screening strategy was utilized, in which 4500 compounds chosen on the basis of structural similarities to known biogenic amine receptor antagonists were tested against both the D4 and D2 dopamine receptor subtypes. A potent D4-selective compound was discovered.