Isoquinolinone derivatives as potent CNS multi-receptor D2/5-HT1A/5-HT2A/5-HT6/5-HT7 agents: Synthesis and pharmacological evaluation
Graphical abstract
Introduction
Schizophrenia is characterized by positive, negative, and cognitive symptoms. Approximately 20% of diagnosed individuals have permanent and severe symptoms that cause disability, and more than 50% have non-persistent symptoms that follow a long course.[1] Current antipsychotics (Cozapine, Olanzapine, Risperidone, etc, Fig. 1) are marginally effective in treating positive symptoms but are less effective against negative symptoms and cognitive dysfunction. Furthermore, the treatment of schizophrenia with antipsychotics is impaired by a number of side effects, such as motor side effects, weight gain, metabolic disturbances, cardiovascular risk factors, and abnormalities in prolactin secretion.[[2], [3], [4], [5], [6]] Therefore, novel drug types that are effective against not only positive symptoms but also negative symptoms and cognitive impairment would represent a significant advancement in schizophrenia treatment.
In our previous study, we found that compounds A–D exerted obvious multi-target characteristics (Fig. 2).[[7], [8], [9], [10]] As shown in Table 1, Compared to compounds A-C, compound D exhibited high affinity for D2, D3, 5-HT1A, and 5-HT2A, but also had strong binding affinity to the 5HT6 receptor. Moreover, compound D was not only effective in the animal model of positive symptoms, but also significantly displayed procognition properties in a novel object recognition task in rats.[10] Compound D received China Food and Drug Administration (CFDA) approval for clinical trials in 2018. Aripiprazole was approved by the Food and Drug Administration for treatment of schizophrenia in 2002. Aripiprazole exhibits high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors, as well as moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1 adrenergic, and histamine H1 receptors. Aripiprazole functions as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and as an antagonist at the serotonin 5-HT2A receptor.[11] Therefore, it is considered to be a dopamine-serotonin system stabilizer, which has not been observed in the activity of any other antipsychotic drug.[12] Brexpiprazole is a partial agonist of 5-HT1A and D2 receptors with Ki values of 0.12 nM and 0.3 nM, respectively, as well as a 5-HT2A receptor antagonist with a Ki of 0.47 nM.[13] RP5063, a novel multimodal dopamine and 5-HT modulator, shows high affinity for D2,3,4 and 5-HT2A,2B,7 receptors. As an adjunctive treatment, RP5063 has multifaceted effects in improving some of the cognitive deficits associated with schizophrenia.[14] These observations encouraged us to design multi-target ligands that can precisely modulate the activity of several monoaminergic receptors (dopamine D2 and serotonin 5-HT1A, 5-HT2A, 5-HT6, and 5-HT7 receptors), expecting that this multifunctional profile will contribute to the therapeutic potential for patients with schizophrenia.
Aripiprazole, brexpiprazole, and RP5063 contain lactam, with high affinity to 5-HT1A, 5HT7 and D2 receptors. In this study, a new compound was designed to form lactam by reversing an amide bond (Fig. 3) and linking to an arylpiperazine (piperidine) group, which is one of the most important classes for CNS activity.[15] A series of new compounds were produced with an appropriate linker between the lactam molecule and privilege structures (Table 1, Table 2, Table 3), and structure-activity relationship studies and competitive receptor-binding assays were performed to evaluate their pharmacological efficacy and relative affinity for the multi-receptor, respectively. The target compounds were subjected to preliminary pharmacological evaluation to determine their affinity for D2, 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, and H1 receptors. Compound 13 exhibited higher affinity for D2, 5-HT1A, 5-HT2A, 5-HT6, and 5-HT7 receptors and low affinity for H1 and 5-HT2C receptors. Furthermore, compound 13 reduced apomorphine-induced climbing in animal behavioral studies as well as MK-801-induced hyperactivity, with a high threshold for inducing catalepsy. In addition, compound 13 lead to negligible weight gain and did not significantly influence serum prolactin levels compared with risperidone. Moreover, compound 13 displayed procognitive properties in a novel object recognition task in rats and showed favorable pharmacokinetic properties. Compared to compounds A-D, compound 13 showed also antipsychotic-like effects in vivo models in low doses, and it was also found effective in anti-depressant and procognitive tests. Thus, compound 13 was used to validate our novel approach to atypical antipsychotics based on its unique polypharmacological antipsychotic profile.
Section snippets
Chemistry
The general strategy for the synthesis of the studied compounds is summarized in Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, Scheme 6. As shown in Scheme 1, intermediate 2 was obtained under triethylamine conditions with ethoxyphenylamine and ethyl chloroformate. Under P2O5 and methanesulfonic acid conditions, intermediate 2 self-condensed to obtain intermediate 3, and reacted with iodomethane to obtain intermediate 4. Intermediate 4 was demethylated under HBr conditions to obtain
Conclusion
In summary, we here described the synthesis and pharmacological evaluation of a series of Isoquinolinone derivatives as potential multi-target antipsychotics. Among the derivatives synthesized, compound 13 showed high affinity for dopamine D2 and serotonin 5-HT1A, 5-HT2A, 5-HT6, and 5-HT7 receptors, and a satisfactory selectivity profile for non-target receptors (5-HT2C, H1, and α1) that have been closely linked to the negative side effects of other marketed antipsychotics. In vivo animal
Experimental section
Chemistry. All commercially available chemicals and reagents were used without further purification. Reagents were all of analytical grade or of chemical purity (>95%). Melting points were determined in open capillary tubes and are uncorrected. 1H NMR spectra was recorded on a Bruker Avance III 600 spectrometer at 400 MHz (1H) using CDCl3 as solvent. Chemical shifts were given in d values (ppm), using tetramethylsilane (TMS) as the internal standard; coupling constants (J) were given in Hz.
General procedures for the binding assays
All of the new compounds were solved in 50% (v/v) DMSO, and the compound concentration was 2 × 10−3 M; dilution to the initial concentration of the new compound, 2 × 10−4 M, contained 5% DMSO. The following specific radioligands and tissue sources were used:
(a) the serotonin 5-HT1A receptor, [3H]8-OH-DPAT, from rat brain cortex; (b) the serotonin 5-HT2A receptor, [3H]ketanserin in the present of 4-dione hydrochloride hydrate (35 nM), from rat brain cortex; (c) the serotonin 5-HT2C receptor, [3
Animals
Chinese Kun Ming (KM) Mice (20 ± 2.0 g) and Sprague-Dawley (SD) rats (250 ± 5.0 g) were used as experimental animals in this study. Animals were housed under standardized conditions for light and temperature and received standard rat chow and tap water and libitum. Animals were randomly assigned to different experimental groups, each kept in a separate cage. All studies involving animals in this research follow the guidelines of the bylaw of experiments on animals and have been approved by the
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.
Acknowledgements
We are grateful for financial support from the NSFC (grant 81602971) and Six Talent Peak project in Jiangsu Province (grant 2019-SWYY-128). We are grateful for support Jiangsu Nhwa Pharmaceutical Co., Ltd and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.
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Jian Jin, Kunxiao Zhang and Fei Dou contributed equally to this work.