Synthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics

doi:10.1016/j.ejmech.2014.01.012

European Journal of Medicinal Chemistry

Volume 74, 3 March 2014, Pages 427-439

https://doi.org/10.1016/j.ejmech.2014.01.012 Get rights and content

Highlights

•
A series of coumarin derivatives were synthesized.
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The targeted compounds were evaluated affinity for D₂, 5-HT_1A and 5-HT_2A receptors.
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Selected compounds were evaluated affinity for D₃ and H₁ receptors.
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In addition, the most active compounds were tested in vivo animal model.

Abstract

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.

Graphical abstract

A series of new coumarin derivatives have been synthesized and the target compounds evaluated for atypical antipsychotic activity in vitro and vivo.

Introduction

Schizophrenia is a chronic incapacitating syndrome that affects 1% of the population [1]. First generation anti-psychotic drugs (APs) are dopamine 2 (D₂) receptor antagonists. While effective in reducing positive symptoms, these drugs are ineffective in treating negative symptoms and cognitive dysfunction and commonly cause extrapyramidal syndrome (EPS) [2], [3], [4]. Second generation APs (e.g., clozapine, ziprasidone and risperidone, Fig. 1) target the D₂ receptor, as well as other receptors and have a lower incidence of EPS [5]. However, a major issue with many atypical antipsychotics is their association with numerous side effects, including substantial weight gain and QT interval prolongation [6], [7], [8], [9]. Therefore, there is a tremendous unmet need for new antipsychotic medications that effectively treat all aspects of the disease, while possessing a side-effect profile that poses little challenge to compliance.

During the past decade, experimental evidence suggested that a complex binding profile is linked to the clinical efficacy of antipsychotic drugs. Indeed, the importance of designing multi-target G-protein-coupled receptors to deal with schizophrenia has been pointed out by many studies [10], [11], [12]. The serotoninergic system plays a variety of roles in the regulation of the prefrontal cortex (PFC) and is highly associated with emotional control, sleep, mood, cognitive behavior and memory [13], [14]. The pyramidal neurons of the PFC possess numerous serotoninergic receptors, including 5-HT_1A and 5-HT_2A receptors [15]. Several studies have shown that activation of 5-HT_1A receptor increases dopamine release in the frontal cortex, which may improve negative symptoms and cognitive deficits in schizophrenia [16]. Serotonin acting at 5-HT_2A receptor, inhibits neuronal activity in the substantia nigra and ventral tegmental areas. A growing number of studies have reported that 5-HT_2A receptor antagonists increase the activity of nigrostriatal DA-containing neurons following moderate D₂ receptor blockade associated with antipsychotic drugs [17], [18]. The blockade of 5-HT_2A receptors has been implicated in both the enhanced efficacy against negative schizophrenic symptoms and improved EPS profile of the atypical antipsychotics [19]. Dopamine plays important roles in behavior and cognition in the central nervous system (CNS) [20]. Blockade of mesolimbic D₂ receptor increases the efficacy of atypical antipsychotics against positive symptoms associated with schizophrenia [21]. The role of D₃ receptor in antipsychotic therapy is currently unknown; however, D₃ antagonists may enhance acetylcholine release in the frontal cortex, thereby improving cognitive deficits. A growing number of preclinical studies suggest that the D₃ receptor may be a useful target for amelioration of the negative and cognitive symptoms associated with schizophrenia and substance abuse disorders [22], [23], [24], [25]. Moreover, H₁ receptor may be involved in the weight gain associated with the treatment of schizophrenia via atypical antipsychotic drugs [26], [27]. Thus, the aim of our work is to develop a novel antipsychotics that acts on dopamine D₂ and D₃, serotonin 5-HT_1A and 5-HT_2A receptors with a low affinity for the H₁ receptor, so that it could effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect.

In our previous study, coumarin derivatives showed obviously antipsychotic activity. Compound 1 possesses high affinity for dopamine D₂, D₃ and serotonin 5-HT_1A, 5-HT_2A receptors, and it possesses low affinity for H₁ receptor (to reduce the risk of obesity associated with chronic treatment) [28]. Furthermore, compound 1 exhibited obviously antipsychotic without observable catalepsy in animal models. In order to expand the structure–activity relationships of coumarin derivatives, the present study focused on the synthesis and pharmacological evaluation of a new class of antipsychotic agents which connect 3-position and 4-position into ring derivatives (Fig. 2). The target compounds were subjected to preliminary pharmacological evaluation to determine their affinity for D₂, D₃, 5-HT_1A, 5-HT_2A and H₁ receptors. The appropriate compounds have to be chosen here for the basic behavioral screening of their atypical antipsychotic potency.

Section snippets

Chemistry

The synthesis of the novel coumarin derivatives was performed according to the reaction pathways illustrated in Schemes 1 and 2. The 2-carboalkoxcyclohexanone derivatives (4) were synthesized, exploiting the Dieckmann condensation of the corresponding pimelic esters (3) (Scheme 1) by treatment with AlCl₃ and triethylamine; this provided a good yield [29]. Subsequently, 2-carboalkoxcyclohexanone derivatives (4) reacted with substituted resorcinol via the Pechmann reaction to give

In vitro studies

All the new compounds were dissolved in 5% DMSO. The following specific radioligands and tissue sources were used: (a) serotonin 5-HT_1A receptor, [³H]8-OH-DPAT, rat brain cortex; (b) serotonin 5-HT_2A receptor, [³H]ketanserin, rat brain cortex; (c) serotonin 5-HT_2C receptor, [³H]mesulergine, rat brain cortex; (d) dopamine D₂ receptor, [³H]spiperone, rat striatum; (e) dopamine D₃ receptor, [³H] 7-OH-DPAT, rat olfactory tubercle; (f) histamine H₁ receptor, [³H]mepyramine, guinea pig cerebellum;

In vitro studies of new compounds

In this work, our initial design focus was to investigate the effect of different amine moieties for the affinities to D₂, 5-HT_1A and 5-HT_2A receptors (Table 1, compounds 7–19). As shown in Table 1, when amine moieties were phenylpiperazine, 2,3-dichlorophenylpiperazine, 4-trifluorophenylpiperazine, 2,3-dimethylphenylpiperazine and 3-trifluoromethyl phenylpiperazine, compounds 7–11 exhibited good affinities for the 5-HT_1A and 5-HT_2A receptors, but showed weak activity for the D₂ receptor.

Conclusion

In summary, we described the synthesis and pharmacological evaluation of a series of coumarin derivatives as potential multi-target antipsychotics. Among the derivatives synthesized, compound 27 showed high affinity for dopamine D₂ and D₃, serotonin 5-HT_1A, 5-HT_2A receptors, with a low affinity for the H₁ receptor. In vivo animal models showed that compound 27 had high potential for treating symptoms of schizophrenia without causing catalepsy. Compound 27 had a higher threshold for catalepsy

Chemistry experimental

Melting points were determined in open capillary tubes and are uncorrected. ¹H NMR spectra were recorded at 400 MHz on a Varian Inova Unity 200 spectrometer in CDCl₃ solution. Chemical shifts were given in δ values (ppm), using tetramethylsilane (TMS) as the internal standard; coupling constants (J) were given in Hz. Signal multiplicities were characterized as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad signal). Reagents were all of analytical grade or of

Acknowledgments

The authors gratefully acknowledge the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program” (2012ZX09103-101-010)

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Original articleSynthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

In vitro studies

In vitro studies of new compounds

Conclusion

Chemistry experimental

Acknowledgments

Psychoneuroendocrinology

Curr. Opin. Pharmacol.

Pharmacol. Ther.

Trends Pharmacol. Sci.

Behav. Brain Res.

Pharmacol. Ther.

Neuropharmacology

Neurosci. Biobehav. Rev.

Tetrahedron

Tetrahedron Lett.

Behav. Brain Res.

Eur. J. Med. Chem.

Annu. Rev. Pharmacol. Toxicol.

Schizophr. Res.

Annu. Rev. Neurosci.

BMJ

Psychopharmacology

CNS Drugs

Original article
Synthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics