Stevin H. Zorn

Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile

Ziprasidone is a novel antipsychotic agent with a unique combination of pharmacological activities at human receptors. Ziprasidone has high affinity for human 5-HT receptors and for human dopamine D(2) receptors. Ziprasidone is a 5-HT(1A) receptor agonist and an antagonist at 5-HT(2A), 5-HT(2C) and 5-HT(1B/1D) receptors. Additionally, ziprasidone inhibits neuronal uptake of 5-HT and norepinephrine comparable to the antidepressant imipramine. This unique pharmacological profile of ziprasidone may be related to its clinical effectiveness as a treatment for the positive, negative and affective symptoms of schizophrenia with a low propensity for extrapyramidal side effects, cognitive deficits and weight gain.

Asenapine: a novel psychopharmacologic agent with a unique human receptor signature:

Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder. We determined and compared the human receptor binding affinities and functional characteristics of asenapine and several antipsychotic drugs. Compounds were tested under comparable assay conditions using cloned human receptors. In comparison with the antipsychotics, asenapine showed high affinity and a different rank order of binding affinities (pK i) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8], 5-HT2C [10.5], 5-HT 5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors (α1 [8.9], α2A [8.9], α2B [9.5] and α2C [8.9]), dopamine receptors (D1 [8.9], D 2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]). It had much lower affinity (pK i ≤ 5) for muscarinic receptors and was the only agent with affinity for H2 receptors. Relative to its D2 receptor affinity, asenapine had a higher affinity for 5-HT 2C, 5-HT2A, 5-HT2B, 5-HT7, 5-HT 6, α2B and D3 receptors, suggesting stronger engagement of these targets at therapeutic doses. Asenapine behaved as a potent antagonist (pK B) at 5-HT1A (7.4), 5-HT 1B (8.1), 5-HT2A (9.0), 5-HT2B (9.3), 5-HT 2C (9.0), 5-HT6 (8.0), 5-HT7 (8.5), D2 (9.1), D3 (9.1), α2A (7.3), α2B (8.3), α2C (6.8) and H1 (8.4) receptors. These functional effects differed from those of risperidone (pK B < 5 for 5-HT6) and olanzapine (pK B < 5 for 5-HT 1A and α2). Our results indicate that asenapine has a unique human receptor signature, with binding affinity and antagonistic properties that differ appreciably from those of antipsychotic drugs.

Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation

Clozapine (1-10 mg/kg s.c.) produces a selective increase in dopamine release in rat prefrontal cortex which is, in large part (approximately 50%), mediated via activation of 5-HT1A receptors. Clozapine is a moderately potent, partial 5-HT1A receptor agonist and activation of 5-HT1A receptors may contribute to its efficacy against negative symptoms and reduced extrapyramidal side effect liability. Agonist affinity for 5-HT1A receptors could thus be a desirable feature in the design of new antipsychotics.

5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex

Background: Ziprasidone (Zeldox) is a novel antipsychotic with a unique combination of antagonist activities at monoaminergic receptors and transporters and potent agonist activity at serotonin 5-HT1A receptors. 5-HT1A receptor agonism may be an important feature in ziprasidone’s clinical actions because 5-HT1A agonists increase cortical dopamine release, which may underlie efficacy against negative symptoms and reduce dopamine D2 antagonist-induced extrapyramidal side effects. This study investigated the in vivo 5-HT1A agonist activity of ziprasidone by measuring the contribution of 5-HT1A receptor activation to the ziprasidone-induced cortical dopamine release in rats. Methods: Effects on dopamine release were measured by microdialysis in prefrontal cortex and striatum. The role of 5-HT1A receptor activation was estimated by assessing the sensitivity of the response to pretreatment with the 5-HT1A antagonist, WAY-100635. For comparison, the D2/5-HT2A antagonists clozapine and olanzapine, the D2 antagonist haloperidol, the 5-HT2A antagonist MDL 100,907 and the 5-HT1A agonist 8-OHDPAT were included. Results: Low doses (<3.2 mg/kg) of ziprasidone, clozapine, and olanzapine increased dopamine release to approximately the same extent in prefrontal cortex as in striatum, but higher doses (≥3.2 mg/kg) resulted in an increasingly preferential effect on cortical dopamine release. The 5-HT1A agonist 8-OHDPAT produced a robust increase in cortical dopamine (DA) release without affecting striatal DA release. In contrast, the D2 antagonist haloperidol selectively increased striatal DA release, whereas the 5-HT2A antagonist MDL 100,907 had no effect on cortical or striatal DA release. Prior administration of WAY-100635 completely blocked the cortical DA increase produced by 8-OHDPAT and significantly attenuated the ziprasidone- and clozapine-induced cortical DA increase. WAY-100635 pretreatment had no effect on the olanzapine-induced DA increase. Conclusions: The preferential increase in DA release in rat prefrontal cortex produced by ziprasidone is mediated by 5-HT1A receptor activation. This result extends and confirms other in vitro and in vivo data suggesting that ziprasidone, like clozapine, acts as a 5-HT1A receptor agonist in vivo, which may contribute to its activity as an antipsychotic with efficacy against negative symptoms and a low extrapyramidal side effect liability.

Clozapine is a potent and selective muscarinic M4 receptor agonist

Clozapine was studied in functional assays at human muscarinic M1-M5 receptors expressed in Chinese hamster ovary cells. Clozapine was a full agonist at the muscarinic M4 receptor (EC50 = 11 nM), producing inhibition of forskolin-stimulated cAMP accumulation. In contrast, clozapine potently antagonized agonist-induced responses at the other four muscarinic receptor subtypes. Selective stimulation of M4 receptors may, in part, explain the hypersalivation observed clinically with clozapine. Moreover, the unique overall muscarinic profile of clozapine may contribute to its atypical antipsychotic efficacy.

Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition

Abstract Recent evidence suggests that the dopamine D4 receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D4 dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1–5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D4-selective compounds, CP-293,019 (5.6–17.8 mg/kg), U-101,387 (3–30 mg/kg) and L-745,870 (1–10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D4 dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D2 receptor antagonists.

Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation.

Ziprasidone is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 μg/kg IV) as did the atypical antipsychotics clozapine (ED50 = 250 μg/kg IV) and olanzapine (ED50 = 1000 μg/kg IV). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 μg/kg IV) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to α1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of α1 antagonists on raphe unit activity. DMI (5 mg/kg IV) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and α1 antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions.

Synthesis, sar and pharmacology of CP-293,019 : A potent, selective dopamine D4 receptor antagonist

A series of novel, potent and selective pyrido[1,2-a]pyrazine dopamine D4 receptor antagonists are reported including CP-293,019 (D4 Ki = 3.4 nM, D2 Ki > 3,310 nM), which also inhibits apomorphine-induced hyperlocomotion in rats after oral dosing.

A new class of selective and potent inhibitors of neuronal nitric oxide synthase.

The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.

A water soluble benzazepine cholecystokinin-B receptor antagonist

Abstract A series of 5-substituted-3-ureidobenzazepin-2-ones bearing ioizable functionality was synthesized as potential cholecystokinin-B (CCK-B) receptor antagonists. SAR of this series of compounds demonstrated the optimal combination of a carboxylic acid and 5-cyclohexyl group, providing the high affinity (CCK-B IC 50 = 0.10 nM), water soluble CCK-B antagonist 2 .