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Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments.

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H 3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D 2 , D 3 , 5-HT 1A , 5-HT 2A and H 3 , a moderate affinity for 5-HT 6 , negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT 2C , adrenergic α 1 and H 1 ). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cocrystallization is an important route to tuning the solubility in drugs development, including improving and reducing. Five cocrystals of aripiprazole (ARI) with resveratrol (RSV) and kaempferol (KAE), ARI-RSV, ARI 2 -RSV 1 ·MeOH, ARI-KAE, ARI-KAE·EtOH, ARI-KAE·IPA, were synthesized and characterized. The single crystal of ARI 2 -RSV 1 ·MeOH, ARI-KAE·EtOH, and ARI-KAE·IPA were analyzed by single crystal X-ray diffraction (SCXRD). The SCXRD showed multiple intermolecular interactions between API and the coformers, including hydrogen bond, halogen bond, and π-π interactions. Dissolution rate of the two nonsolvate ARI-RSV and ARI-KAE cocrystals were investigated through powder dissolution experiment in pH = 4.0 acetate buffer and pH = 6.8 phosphate buffer. The result showed that RSV could reduce the dissolution rate and solubility of ARI in both medium through cocrystallization. However, KAE improved the dissolution rate and solubility of ARI in pH = 4.0 medium, on the contrary, the two solubility indicators of ARI were both reduced for ARI-KAE cocrystal.

In this study, a series of novel Isoquinolinone derivatives were synthesized as potential multi-target antipsychotics. Among these, compound 13 showed high affinity for dopamine D 2 and serotonin 5-HT 1A , 5-HT 2A , 5-HT 6 , and 5-HT 7 receptors, showed low affinity for off-target receptors (5-HT 2C , H 1 , and α 1 ), and negligible effects on ether-a-gogo-related gene (hERG; i.e., reduced QT interval prolongation). An animal behavioral study revealed that compound 13 reversed APO-induced hyperlocomotion, MK-801-induced hyperactivity, and DOI-induced head twitch. Moreover, compound 13 exhibited a high threshold for acute toxicity, a lack of tendency to induce catalepsy, and did not cause prolactin secretion or weight gain when compared to risperidone. Furthermore, in the forced swim test, tail suspension test, and novel object recognition test, treatment with compound 13 resulted in improvements in depression and cognitive impairment. In addition, compound 13 had a favorable pharmacokinetic profile in rats. Thus, the antipsychotic drug-like effects of compound 13 indicate that it may be useful for developing a novel class of drugs for the treatment of schizophrenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one ( 6j ) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D 2 , D 3 , and serotonin 5-HT 1A , 5-HT 2A receptors, but was also endowed with low to moderate activities on 5-HT 2C , α 1 , and H 1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.

A potent antipsychotic drug candidate, 7-(4-(4-(6-fluorobenzo[d]-isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro -2H-chromen-2-one mesylate(CY611), with good in vitro and in vivo antipsychotic effects was investigated for preformulation evaluation by crystallography methods. Three anhydrous polymorphs(Form I-III), a monohydrate(Form IV), and a NMP solvate(Form V) were discovered and characterized by powder X-ray diffraction, thermal analysis, attenuated total reflection-fourier transform infrared spectroscopy and scanning electron microscopy. Form I, monohydrate Form IV, and a NMP solvate Form V of the drug candidate were isolated, and their structures were determined by single crystal X-ray diffraction. IDR and relative stability experiment were performed. Although Form II has the fastest release rate in water, it easy transformed to monohydrate which has the lowest release rate. In vivo pharmacokinetic study showed that the Form III has the highest bioavailability at 35.4%. Considering the balance between the physicochemical properties, bioavailability and manufacturability of the available polymorphs, Form III may be the optimal form candidate for the eventual formulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Herein, a novel series of multireceptor ligands was developed as polypharmacological antipsychotic agents using the designed multiple ligand approach between dopamine receptors and serotonin receptors. Among them, compound 47 possessed unique pharmacological features, exhibiting high affinities for D 2 , D 3 , 5-HT 1A , 5-HT 2A , and 5-HT 6 receptors and low efficacy at the off-target receptors (5-HT 2C , histamine H 1 , and adrenergic α 1 receptor). Compound 47 showed dose-dependent inhibition of apomorphine- and MK-801-induced motor behavior, and the conditioned avoidance response with low cataleptic effect. Moreover, compound 47 resulted nonsignificantly serum prolactin levels and weight gain change compared with risperidone. Additionally, compound 47 possessed a favorable pharmacokinetic profile with oral bioavailability of 58.8% in rats. Furthermore, compound 47 displayed procognition properties in a novel object recognition task in rats. Taken together, compound 47 may constitute a novel class of atypical antipsychotic drugs for schizophrenia.

In this paper, we report the synthesis of novel, potential antipsychotic coumarin derivatives combining potent dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors properties. We describe the structure activity relationship that leads us to the promising derivative: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-6-methyl-2,3-dihydrocyclopenta[c]chromen-4(1H)-one 27. The unique pharmacological features of compound 27 are a high affinity for dopamine D₂, D₃ and serotonin 5-HT(1A), 5-HT(2A) receptors, together with a low affinity for H₁ receptor (to reduce the risk of obesity under chronic treatment). In animal models, compound 27 inhibited apomorphine-induced climbing and MK-801-induced hyperactivity without observable catalepsy at the highest dose tested. In particular, compound 27 was more potent than clozapine., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1A and 5-HT2A receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C 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 17m 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 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.

In this paper, we report the discovery and the synthesis of novel, potential antipsychotic piperidine-2,6-dione derivatives combining potent dopamine D(2) , D(3) and serotonin 5-HT(1A) , 5-HT(2A) , 5-HT(2C) receptor properties. We describe the structure-activity relationships that led us to the promising derivative: 1-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butyl)-4-(4-chlorophenyl)-piperidine-2,6-dione 5. The unique pharmacological features of compound 5 are a high affinity for dopamine D(2) , D(3) and serotonin 5-HT(1A) , 5-HT(2A) , 5-HT(2C) receptors, together with a low affinity for the H(1) receptor (to reduce the risk of obesity under chronic treatment). In a behavioral model predictive of positive symptoms, compound 5 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. In particular, compound 5 was more potent than clozapine., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D(2) and D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors with low affinity for the serotonin 5-HT(2C) and H(1) receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect., Methodology/principal Findings: A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D(3) receptor, and low affinity for serotonin 5-HT(2C) and H(1) receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties., Conclusions/significance: Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.

Dopamine D 3 receptor (D 3 R) is implicated in multiple psychotic symptoms. Increasing the D 3 R selectivity over dopamine D 2 receptor (D 2 R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D 3 R selective ligands. Through a structure-based virtual screen, ZLG-25 (D 3 R K i = 685 nmol/L; D 2 R K i > 10,000 nmol/L) was identified as a novel D 3 R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D 3 R-selective analogs with tetrahydro- β -carboline or tetrahydro- γ -carboline core. Further functional studies showed that most derivatives acted as hD 3 R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties. Novel carbazole and tetrahydro-carboline derivatives were discovered as D 3 R selective antagonists through the structure-based virtual screen and scaffolds hopping, which were identified with the multiple antipsychotic-like and favorable drug-like properties. [Display omitted] [ABSTRACT FROM AUTHOR]

In recent years, multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics. Combinations of dopamine and serotonin receptor ligands within single molecules might afford new therapeutic opportunities. Herein, we describe the synthesis of a novel series of 6-hydroxypyridazinone benzisoxazoles and their binding behaviors to different receptors in terms of atypical antipsychotic behaviors. The most potent compound (46) exhibited excellent affinities for certain receptors (D 2 , K i = 0.5 ± 0.07 nM; 5-HT 1A , K i = 5.9 ± 0.8 nM; 5-HT 2A , K i = 0.3 ± 0.01 nM; 5-HT 6 , K i = 0.5 ± 0.04 nM) and combined with low affinities for the H 1 , 5-HT 2C , and adrenergic α 1 receptors. In contrast to risperidone, compound 46 exhibited a high cataleptic threshold; this may be useful in the development of a novel class of drugs treating schizophrenia. [ABSTRACT FROM AUTHOR]