Plasma pharmacokinetic data following administration of compound 22 (i.v. dose of 5 mg/kg and p.o. dose of 20 mg/kg) in rats (n = 6/group).

<p>Plasma pharmacokinetic data following administration of compound 22 (i.v. dose of 5 mg/kg and p.o. dose of 20 mg/kg) in rats (n = 6/group).</p

Structure of compounds 7–26.

<p>Structure of compounds 7–26.</p

Synthesis of compounds 7–26.

<p>Synthesis of compounds 7–26.</p

Binding affinities for D₂, D₃, 5-HT_1A, 5-HT_2A, 5-HT_2C and H₁ receptors of compounds 7–26 and reference antipsychotics.^a

a<p>Ki values are taken from three experiments, expressed as means ±SEM.</p>b<p>The Ki values were not calculated because the inhibition percentages at 10 µM were too low.</p

Title and reference compounds.

<p>Title and reference compounds.</p

In <i>vivo</i> pharmacological profile of compound 22. Inhibition of different behavioral responses after oral administration of the test and reference Compounds.

a<p>95% Confidence limits given in parentheses.</p

Table1_Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia.DOCX

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia.Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical.Results:In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094.Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.</p

Image1_Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia.tif

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia.Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical.Results:In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094.Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.</p

Synthesis and Biological Investigation of Coumarin Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical Antipsychotics

The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D₂, D₃, and serotonin 5-HT_1A and 5-HT_2A receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo­[<i>d</i>]­isoxazol-3-yl)-piperidin-1-yl)­butoxy)-4-methyl-8-chloro-2<i>H</i>-chromen-2-one (<b>17m</b>). This derivative possesses unique pharmacological features, including high affinity for dopamine D₂ and D₃ and serotonin 5-HT_1A and 5-HT_2A receptors. Moreover, it possesses low affinity for 5-HT_2C and H₁ receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound <b>17m</b> inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with <b>17m</b> compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with <b>17m</b>. Taken together, <b>17m</b> may constitute a novel class of drugs for the treatment of schizophrenia