Isoquinolinone derivatives as potent CNS multi-receptor D₂/5-HT_1A/5-HT_2A/5-HT₆/5-HT₇ agents: Synthesis and pharmacological evaluation

Abstract

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 D₂ and serotonin 5-HT_1A, 5-HT_2A, 5-HT₆, and 5-HT₇ receptors, showed low affinity for off-target receptors (5-HT_2C, H₁, and α₁), 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.

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-HT_1A, and 5-HT_2A, 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-HT_1A and 5-HT_2A receptors, as well as moderate affinity for dopamine D₄, serotonin 5-HT_2C and 5-HT₇, alpha-₁ adrenergic, and histamine H₁ receptors. Aripiprazole functions as a partial agonist at dopamine D₂ and serotonin 5-HT_1A receptors, and as an antagonist at the serotonin 5-HT_2A 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-HT_1A and D₂ receptors with K_i values of 0.12 nM and 0.3 nM, respectively, as well as a 5-HT_2A receptor antagonist with a K_i of 0.47 nM.[13] RP5063, a novel multimodal dopamine and 5-HT modulator, shows high affinity for D_2,3,4 and 5-HT_2A,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-HT_1A, 5-HT_2A, 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-HT_1A, 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-HT_1A, 5-HT_2A, 5-HT₆, 5-HT₇, and H₁ receptors. Compound 13 exhibited higher affinity for D₂, 5-HT_1A, 5-HT_2A, 5-HT₆, and 5-HT₇ receptors and low affinity for H₁ and 5-HT_2C 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.