Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders.

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer's disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type.

Safety, Tolerability and Pharmacokinetics of the Serotonin 5-HT6 Receptor Antagonist, HEC30654, in Healthy Chinese Subjects.

Background and Objective: HEC30654 is a selective 5-HT6 receptor antagonist that was safe and well-tolerated in preclinical models of Alzheimer's disease. The objective of this double-blind, randomized, placebo-controlled clinical trial was to evaluate the safety, tolerability, and pharmacokinetic profile of HEC30654 after single ascending doses in healthy Chinese subjects. Methods: Healthy volunteers received a single oral dose of HEC30654 (5, 10, 15, 30, 60 mg). Safety and tolerability assessments included adverse events, vital signs, and findings on electrocardiograms, electroencephalograms, physical examination, and clinical laboratory tests. Pharmacokinetic analysis of HEC30654 and its major metabolite HEC93263 were conducted in blood, urine, and fecal samples. Results: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated, but dose escalation was terminated early as the 60 mg HEC30654 treatment group met the pre-defined stopping rules specified in the protocol. Median tmax of HEC30654 was 6 h (range, 4-12 h), t1/2 of 10-60 mg HEC30654 ranged from 52.1 to 63.8 h. Exposure to HEC30654 across the dose range explored in this study increased more than in proportion to dose. Metabolism of HEC30654 to HEC93263 was slow (<10%), and HEC30654 was mainly eliminated unchanged through feces. Conclusion: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated. Based on preclinical efficacy in various models of cognition, HEC30654 may represent a therapeutic option for symptomatic treatment of cognitive disorders.

Clinical Research on Alzheimer's Disease: Progress and Perspectives.

Alzheimer's disease (AD), the most common type of dementia, is becoming a major challenge for global health and social care. However, the current understanding of AD pathogenesis is limited, and no early diagnosis and disease-modifying therapy are currently available. During the past year, significant progress has been made in clinical research on the diagnosis, prevention, and treatment of AD. In this review, we summarize the latest achievements, including diagnostic biomarkers, polygenic hazard score, amyloid and tau PET imaging, clinical trials targeting amyloid-beta (Aß), tau, and neurotransmitters, early intervention, and primary prevention and systemic intervention approaches, and provide novel perspectives for further efforts to understand and cure the disease.

Idalopirdine, a selective 5-HT6 receptor antagonist, reduces food intake and body weight in a model of excessive eating.

Obesity, from early childhood onwards, is a common societal problem. The overconsumption of sweet, salty and high-fat products are the main factors that cause excessive weight gain. It is therefore necessary to search for new drugs that affect satiety centers and reduce the sense of hunger and caloric intake. It has been suggested that the blockade of 5-HT6 receptors may reduce food intake, and since idalopirdine is a clinically tested, selective 5HT6 receptor antagonist, it was chosen to be examined in animal models of obesity. The activity of idalopirdine was measured in the rat model of excessive eating. Animals were on a high caloric diet that consisted of milk chocolate with nuts, cheese, salted peanuts and condensed milk. During a four-week experiment, the rats had constant access to standard feed and water ad libitum. Idalopirdine was administered intraperitoneally at a dose 5 mg/kg b.w./day. To establish whether idalopirdine would effectively suppress the rebound hyperphagia that accompanies refeeding, it was administered after a 20 h food deprivation period. Pica behavior was evaluated after the administration of idalopirdine to confirm that the suppression of food intake was not caused by visceral illness. The effect of the four-week treatment with idalopirdine on the amount of peritoneal adipose tissue, and on lipid and carbohydrate profiles in rats was also examined. The statistical significance was calculated using the one-way ANOVA post-hoc Tukey Multiple Comparison Test or the two-way ANOVA post-hoc Bonferroni Multiple Comparison Test. Idalopirdine significantly reduced caloric intake and prevented the development of obesity in tested animals. Rats, that received idalopirdine, had a smaller amount of adipose tissue in the peritoneum as well as lower glucose, triglyceride and cholesterol levels in comparison to the control group. Moreover, an anorectic action was not caused by abnormalities of the gastrointestinal tract, such as nausea. The obtained results indicate that idalopirdine reduces caloric intake and could be considered for further tests as a potential treatment of obesity.

Clinical Research on Alzheimer's Disease: Progress and Perspectives / 神经科学通报·英文版

Alzheimer's disease (AD), the most common type of dementia, is becoming a major challenge for global health and social care. However, the current understanding of AD pathogenesis is limited, and no early diagnosis and disease-modifying therapy are currently available. During the past year, significant progress has been made in clinical research on the diagnosis, prevention, and treatment of AD. In this review, we summarize the latest achievements, including diagnostic biomarkers, polygenic hazard score, amyloid and tau PET imaging, clinical trials targeting amyloid-beta (Aβ), tau, and neurotransmitters, early intervention, and primary prevention and systemic intervention approaches, and provide novel perspectives for further efforts to understand and cure the disease.

Neuropathic pain-alleviating effects of pyrazole-conjugated arylsulfonamides as 5-HT6 receptor antagonists.

A novel series of arylsulfonylaminomethyl-3-(1-phenyl-5-isopropyl)pyrazoles was evaluated for serotonin receptor subtype 6 (5-HT6R) antagonistic effects in vitro. We also investigated their neuropathic pain-alleviating effects in vivo using a rat spinal nerve ligation (SNL) model. Bicyclic aromatic sulfonamino groups, such as naphthalene and quinolin-substituted derivatives, showed good 5-HT6 inhibitory activity in vitro. Among them, selected compounds, 12 and 13, having 8-quinoylsulfonamino groups, showed potent neuropathic pain-alleviating effects in the rat model.

N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties.

A series of N1-azinylsulfonyl-3-(1,2,3,6,tetrahyrdopyridin-4-yl)-1H-indole derivatives was designed to obtain highly potent 5-HT6 receptor ligands. The study allowed for the identification of 25 (4-{[5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}isoquinoline), a potent and selective 5-HT6 receptor antagonist. The selected compound, was evaluated in vivo in a novel object recognition (NOR) and forced swim (FST) tests in rats, demonstrating distinct pro-cognitive and antidepressant-like properties (MED = 1 mg/kg and 0.1 mg/kg, i.p., respectively). Compound SB-742457, used as comparator, reversed memory deficits in NOR task in similar doses, while in FST it was active in 10-30-fold higher dose (3 mg/kg). In contrast to SB-742457, which was active in Vogel test (MED = 3 mg/kg), compound 25 displayed no anxiolytic activity.

Idalopirdine - a small molecule antagonist of 5-HT6 with therapeutic potential against obesity.

5HT6 receptor antagonists offer the potential for safe and effective drugs against obesity, because they can reduce weight without causing serious side effects in the cardiovascular system. Also, their anorexic effect is associated with reduced food intake via an enhancement of satiety. In the present study we investigated the anorexic effect of idalopirdine (LuAE58054) in a model of obesity induced by high-fat diet. To induce obesity in rats, the animals were treated with feed with a fat content of 40 %. Body weight was controlled and the amount of food and water consumed was determined. The influence of the test compound on the lipid profile and glucose level was measured, as well as locomotor activity in home cages on the 20th day of the treatment. LuAE58054, at 5 mg kg(-1)/day i.p., was significantly anorectic in this model of obesity. Animals treated with LuAE58054 weighed 8 and 9.2 % less than the control obese animals on the 12th and 21st days, respectively. It significantly reduced food intake and the amount of peritoneal fat in animals, and reduced the level of triglycerides in plasma. LuAE58054 did not have a statistically significant effect on the spontaneous activity of diet-induced obese rats. The present study clearly demonstrates the effectiveness of LuAE58054 in reducing body weight. This compound is in phase III of clinical trials for the treatment of cognitive deficits associated with Alzheimer's disease and schizophrenia. It is a 5HT6 receptor antagonist and is, therefore, free of those unacceptable side effects that preclude chronic use of anti-obesity drugs with other mechanisms of action. The search for an effective and safe anti-obesity drug is essential for an increasingly obese population; therefore, the anorectic action of LuAE58054 is important and there is a need for more research in this direction.

5-HT6 receptor antagonist attenuates the memory deficits associated with neuropathic pain and improves the efficacy of gabapentinoids.

BACKGROUND: Memory deficit is a co-morbid disorder in patients suffering from neuropathic pain. Gabapentin and pregabalin (gabapentinoids) are among the widely prescribed medications for the treatment of neuropathic pain. Memory loss and sedation are the commonly reported side effects with gabapentinoids. Improving the cognitive functions and attenuating drug-induced side effects may play a crucial role in the management of pain. METHODS: We evaluated the effects of 5-HT6 receptor antagonists on the memory deficits associated with neuropathy. We also studied the effects of 5-HT6 receptor antagonists on the side effects, and the analgesic effects of gabapentinoids. RESULTS: 5-HT6 receptor antagonists attenuated the cognitive deficits in neuropathic rats. Neuropathic rats co-treated with 5-HT6 receptor antagonist and gabapentinoids showed improvement in memory. 5-HT6 receptor antagonists enhanced the analgesic effects of gabapentinoids but had no effect on the motor side effects. The observed effects may not be due to pharmacokinetic interactions. CONCLUSIONS: 5-HT6 receptor antagonist attenuate the cognitive deficits associated with neuropathy, and this effect is also seen when co-treated with gabapentinoids. Since, 5-HT6 antagonists improved the effectiveness of gabapentinoids, reduction in the dosage and frequency of gabapentinoids treatment may reduce the side effects. Combining 5-HT6 receptor antagonist with gabapentinoids may offer a novel treatment strategy for neuropathic pain.

Synthesis and the 5-HT6 receptor antagonistic effect of 3-arylsulfonylamino-5,6-dihydro-6-substituted pyrazolo[3,4]pyridinones for neuropathic pain treatment.

A novel series of 3-arylsulfonylamino-5,6-dihydro-6-substituted-1H-pyrazolo[3,4-c]pyridine-7-ones was designed and synthesized as 5-HT6 ligands. Among the derivatives synthesized, the lead compound, 12b, having piperidine functionality at the 6-position and (1-naphthyl)sulfonamino at the 3-position of the core structure showed the most potent 5-HT6 inhibitory activity in vitro, good stability without CYP liability, and good neuropathic pain alleviation activity in a rat animal model.

Design and synthesis of novel series of 5-HT6 receptor ligands having indole, a central aromatic core and 1-amino-4 methyl piperazine as a positive ionizable group.

The exclusive distribution of 5-HT6 receptor in the brain regions and high affinity for antipsychotic and antidepressant drugs makes 5-HT6 receptor a promising target in treatment of CNS diseases. Based on a pharmacophore model reported in the literature, we designed and synthesized a novel series of 5-HT6 receptor ligands having indole as a central aromatic core and 1-amino-4-methyl piperazine as positive ionizable group. Out of 32 compounds we have successfully identified 10 new compounds as 5-HT6 receptor antagonists. The structure-activity relationship (SAR) studies have been carried out by mapping the compounds with the 3D QSAR model.