Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation.

Modulating the glucose transport in skeletal muscle is a promising strategy for ameliorating glucose homeostasis disorders. However, the complicated mechanisms of glucose transport make it difficult to find compounds therapeutically relevant molecular mechanisms of action, while phenotypic screening is thought to be an alternative approach to mimic the cell state of interest. Here, we report (±)-seneciobipyrrolidine (1a) is first found to enhance glucose uptake in L6 myotubes through phenotype-based screening. Further SAR investigation led to the identfication of compound A27 (EC50 = 2.7 µM). Proteomiic analysis discloses the unique function mechanism of A27 through upregulating the level of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), subsequently enhancing the Akt and AMPK phosphorylation, thereby promoting the glucose uptake. Chronic oral administration of A27 significantly lowers blood glucose and improves glucose tolerance in db/db mice. This work is new research on seneciobipyrrolidine derivatives, providing a promising avenue for ameliorating glucose homeostasis.

New 1,2,4-oxadiazole derivatives with positive mGlu4 receptor modulation activity and antipsychotic-like properties.

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu4 receptor positive allosteric modulatory activity (EC50 = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu1, mGlu2 and mGlu5 receptors, but modulated mGlu7 and mGlu8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu4 PAM ADX88178.

Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3 and 5-HT6 Receptor Antagonist with Antipsychotic and Procognitive Properties.

In line with recent clinical trials demonstrating that ondansetron, a 5-HT3 receptor (5-HT3R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6 receptor (5-HT6R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT3R antagonist and a neutral antagonist 5-HT6R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ, neither 5-HT6R inverse agonist SB399885 nor neutral 5-HT6R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3R antagonism and 5-HT6R antagonism, exemplified by FPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3/5-HT6 receptors and encourage further studies on dual-acting 5-HT3/5-HT6R antagonists for the treatment of psychiatric disorders.

N-Skatyltryptamines-Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential.

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.

A study of the structure-affinity relationship in SYA16263; is a D2 receptor interaction essential for inhibition of apormorphine-induced climbing behavior in mice?

Dopamine (DA) and serotonin (5-HT) receptors are prime targets for the development of antipsychotics. The specific role of each receptor subtype to the pharmacological effects of antipsychotic drugs remains unclear. Understanding the relationship between antipsychotic drugs and their binding affinities at DA and 5-HT receptor subtypes is very important for antipsychotic drug discovery and could lead to new drugs with enhanced efficacies. We have previously disclosed SYA16263 (5) as an interesting compound with moderate radioligand binding affinity at the D2 & D3 receptors (Ki = 124 nM & 86 nM respectively) and high binding affinities towards D4 and 5-HT1A receptors (Ki = 3.5 nM & 1.1 nM respectively). Furthermore, we have demonstrated SYA16263 (5) is functionally selective and produces antipsychotic-like behavior but without inducing catalepsy in rats. Based on its pharmacological profile, we selected SYA16263 (5) to study its structure-affinity relationship with a view to obtaining new analogs that display receptor subtype selectivity. In this study, we present the synthesis of structurally modified SYA16263 (5) analogs and their receptor binding affinities at the DA and 5-HT receptor subtypes associated with antipsychotic action. Furthermore, we have identified compound 21 with no significant binding affinity at the D2 receptor subtype but with moderate binding affinity at the D3 and D4 receptors subtypes. However, because 21 is able to demonstrate antipsychotic-like activity in a preliminary test, using the reversal of apomorphine-induced climbing behavior experiment in mice with SYA16263 and haloperidol as positive controls, we question the essential need of the D2 receptor subtype in reversing apomorphine-induced climbing behavior.

Synthesis and Evaluation of Aryl Substituted Propyl Piperazines for Potential Atypical Antipsychotic Activity.

BACKGROUND: Schizophrenia is a disorder with complex etiology with hyperdopaminergia as the leading underlying cause. Atypical antipsychotics are the agents which do not give rise to significant extrapyramidal side effects and are more effective against negative symptoms of schizophrenia. INTRODUCTION: A new series of chloro-substituted substituted aryloxypiperazine derivatives and their indole based derivatives was designed and evaluated for atypical antipsychotic activity based on established models for combined dopaminergic and serotonergic antagonism. METHODS: The present series of compounds were designed based on 3D similarity studies, synthesized and evaluated for atypical antipsychotic activity in animal models for combined dopaminergic and serotonergic antagonism. The blood-brain barrier penetration potential was assessed from theoretical log BB values computed through an online software program. RESULTS: Theoretical ADME profiling of the designed compounds based on selected physicochemical parameters suggested excellent compliance with Lipinski's rules. The log BB values obtained for the compounds suggested a good potential for brain permeation. Indole substitution contributed towards an improved efficacy over aryloxy analogs. Lead compounds showed a potential for combined dopaminergic and serotonergic antagonism. CONCLUSION: The 5-methoxy indole based compounds 16 and 17 were identified as the lead compounds displaying a potential atypical antipsychotic profile.

Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.

In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D2/D3/5-HT1A/5-HT2A receptors and weak α1 and H1 receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.

Controlling receptor function from the extracellular vestibule of G-protein coupled receptors.

Receptor function is traditionally controlled from the orthosteric binding site of G-protein coupled receptors. Here, we show that the functional activity and signalling of human dopamine D2 and D3 receptor ligands can be fine-tuned from the extracellular secondary binding pocket (SBP) located far from the signalling interface suggesting optimization of the SBP binding part of bitopic ligands might be a useful strategy to develop GPCR ligands with designed functional and signalling profile.

Isoquinolinone derivatives as potent CNS multi-receptor D2/5-HT1A/5-HT2A/5-HT6/5-HT7 agents: Synthesis and pharmacological evaluation.

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-HT1A, 5-HT2A, 5-HT6, and 5-HT7 receptors, showed low affinity for off-target receptors (5-HT2C, 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.

Design, Synthesis and Biological Investigation of Flavone Derivatives as Potential Multi-Receptor Atypical Antipsychotics.

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 D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 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.

Synthesis and pharmacological evaluation of 11-(1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepines with clozapine-like receptor occupancy at dopamine D1/D2 receptor.

Clozapine-like compound without agranulocytosis risk is need to cure the treatment resistant schizophrenia (TRS). We discovered (S)-3 as Clozapine-like dopamine D2/D1 receptor selectivity and improved reactive metabolites formation profile by the modification of piperazine moiety in Clozapine. The optimization of (S)-3 gave compound 5 to be best compound (approximately 10-fold stronger affinity for D2/D1 receptor and similar D2/D1 selectivity ratio with Clozapine). Clozapine-like D2/D1 receptor occupancy profile was proved by in vivo evaluation. In addition, the reactive metabolites derived agranulocytosis risk of compound 5 was considered to be lower than Clozapine. The pharmacology detail of compound 5 is being investigated to develop it for TRS treatment.

Quetiapine and novel PDE10A inhibitors potentiate the anti-BuChE activity of donepezil.

The symptoms of Alzheimer's disease (AD) do not include only memory loss and cognitive decline but also neuropsychiatric manifestation. These AD-related symptoms are usually treated with the aid of antipsychotics; however, their effects on cognition and safety remain unexplored. The present study determines the effects of quetiapine, an atypical antipsychotic, and two imidazo[1,2-a]pyrimidine-based inhibitors of PDE10A on the activity of human cholinesterases. Quetiapine moderately inhibited BuChE (IC50 = 6.08 ± 1.64 µmol/L) but improved the anti-BuChE properties of donepezil by decreasing its IC50 value. Both PDE10A inhibitors were found to possess moderate anti-AChE properties. The combined mixtures of donepezil and imidazo[1,2-a]pyrimidine analogues produce a synergistic anti-BuChE effect which was greater than either compound alone, improving the IC50 value by approximately six times. These favourable interactions between quetiapine, PDE10A inhibitors and clinically approved donepezil, resulting in improved anti-BuChE activity, can lead to a wider variety of potent AD treatment options.

Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics.

We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D2, 5-HT1A, and 5-HT2A receptors, but low affinity for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives.

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.

Design, Synthesis, and Preclinical Evaluation of 3-Methyl-6-(5-thiophenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-ones as Selective GluN2B Negative Allosteric Modulators for the Treatment of Mood Disorders.

Selective inhibitors of the GluN2B subunit of N-methyl-d-aspartate receptors in the ionotropic glutamate receptor superfamily have been targeted for the treatment of mood disorders. We sought to identify structurally novel, brain penetrant, GluN2B-selective inhibitors suitable for evaluation in a clinical setting in patients with major depressive disorder. We identified a new class of negative allosteric modulators of GluN2B that contain a 1,3-dihydro-imidazo[4,5-b]pyridin-2-one core. This series of compounds had poor solubility properties and poor permeability, which was addressed utilizing two approaches. First, a series of structural modifications was conducted which included replacing hydrogen bond donor groups. Second, enabling formulation development was undertaken in which a stable nanosuspension was identified for lead compound 12. Compound 12 was found to have robust target engagement in rat with an ED70 of 1.4 mg/kg. The nanosuspension enabled sufficient margins in preclinical toleration studies to nominate 12 for progression into advanced good laboratory practice studies.

Repurposing of antipsychotics perphenazine for the treatment of endometrial cancer.

Endometrial cancer (EC) is one of the most common and fatal gynecological cancers worldwide, but there is no effective treatment for the EC patients of progesterone resistance. Repurposing of existing drugs is a good strategy to discover new candidate drugs. In this text, perphenazine (PPZ), approved for psychosis therapy, was identified as a potential agent for the treatment of both progesterone sensitive and resistant endometrial cancer for the first time. Specifically, perphenazine exhibited good cell proliferation inhibition in Ishikawa (ISK) and KLE cell lines according to the CCK-8 assay and colony formation assay. It also reduced the cell migration of ISK and KLE cell lines in the light of the transwell migration assay. Annexin-V/PI double staining assay suggested that perphenazine could effectively induce ISK and KLE cell apoptosis. Moreover, results of western blot assay indicated perphenazine obviously inhibited the phosphorylation of Akt. Delightedly, PPZ also could significantly attenuate xenograft tumor growth at both 3 mg/kg and 15 mg/kg in mice without influencing the body weights.

Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation.

Due to the complex and multifactorial nature of bipolar disorder (BD), single-target drugs have traditionally provided limited relief with no disease-modifying effects. In line with the polypharmacology paradigm, we attempted to overcome these limitations by devising two series of multitarget-directed ligands endowed with both a partial agonist profile at dopamine receptor D3 (D3R) and inhibitory activity against glycogen synthase kinase 3 beta (GSK-3ß). These are two structurally unrelated targets that play independent, yet connected, roles in cognition and mood regulation. Two compounds (7 and 10) emerged as promising D3R/GSK-3ß multitarget-directed ligands with nanomolar activity at D3R and low-micromolar inhibition of GSK-3ß, thereby confirming, albeit preliminarily, the feasibility of our strategy. Furthermore, 7 showed promising drug-like properties in stability and pharmacokinetic studies.

Synthesis and biological investigation of triazolopyridinone derivatives as potential multireceptor atypical antipsychotics.

A series of triazolopyridinone derivatives originating from the antidepressant trazodone was designed and pharmacologically evaluated. Most of the compounds with a multireceptor functional profile exhibited high potency at the D2, 5-HT1A, and 5-HT2A receptors. Compounds S1, S3, S9 and S12 were selected for further evaluation of druggable potential. Among these compounds, S1, as a D2 receptor partial agonist, demonstrated very potent inhibition of quipazine-induced head-twitch response, which validated its 5-HT2A receptor antagonistic efficacy in vivo. S1 also demonstrated a dose-dependent effect on PCP-induced hyperactivity when administered orally. Thus, S1 endowed with a triazolopyridinone scaffold represents a valuable lead for the development of novel atypical antipsychotics.

Discovery of aryl-piperidine derivatives as potential antipsychotic agents using molecular hybridization strategy.

Schizophrenia is a chronic, disabling mental disorder that affects about one percent of world's population. Drugs acting on multiple targets have been demonstrated to provide superior efficacy in schizophrenia than agents acting on single target. In this study, based on FW01, a selective potent 5-HT1A receptor agonist discovered via dynamic pharmacophore-based virtual screening, molecular hybridization strategy was employed to optimize its in vitro activity over D2 and 5-HT2A receptors. The optimized compound 9f was found to show dual potent D2 and 5-HT2A receptors antagonistic activity. In addition, compound 9f showed good in vivo metabolic stability with t1/2 of 2 h in ICR mice and good capability to penetrate the blood-brain barrier with Kp value of 4.03. These results demonstrated that the dual D2 and 5-HT1A receptor antagonist 9f could serve as a promising lead compound to discover potent antipsychotic agents.

Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD).

Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant. A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D2 receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT6Rs and 5-HT7Rs (potential pro-cognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M3R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment through pyrrolidin-1-yl-propyl linker. N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-2-sulfonamide showed a substantial affinity for the targets of interest (pKi = 8.32-9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pKB = 7.41-9.03). The lead compound showed a promising profile of antipsychotic-like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg), antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in the forced swim and four-plate tests, respectively). Notably, the novel compound didn't affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-through passive avoidance test) in therapeutically relevant doses, which proved its benign safety profile. The overall pharmacological characteristics of the lead compound outperformed the reference drug quetiapine, making it a promising option for evaluation in the treatment of BPSD.