It is estimated that in patients taking antipsychotic drugs (APDs), metabolic syndrome occurs 2-3 times more often than in the general population. It manifests itself in abdominal obesity, elevated glucose concentration, and dyslipidemia. Despite the high prevalence of this disorder, only a small percentage of patients receive appropriate and effective treatment, and none of the available methods for preventing or treating APD-induced metabolic side effects is satisfactory. A promising supplement to antipsychotic therapy appears to be ligands of the serotonin 6 (5-HT6) receptor. The present study aimed to examine the chronic effects of the selected APDs (haloperidol, risperidone, olanzapine), administered alone and in combination with a selective 5-HT6 agonist (WAY-181187) or antagonist (SB-742457), on weight gain, food intake, serum lipid profile, glucose level, and a spectrum of hormones derived from adipose (leptin, adiponectin) and gastrointestinal (insulin, ghrelin) tissue in rats. SB-742457 inhibited increased weight gain and alleviated hyperglycemia induced by APDs more strongly than did WAY-181187, but also intensified dyslipidemia. WAY-181187 tended to improve the lipid profile, but increased the glucose level. The greatest benefits were obtained when WAY-181187 or SB-742457 were co-administered with haloperidol. It is difficult to assess whether the modification of the serum levels of insulin, leptin, ghrelin, and adiponectin depended on the treatment applied or other drug-independent factors; therefore, further research is needed.

While monoaminergic deficits are evident in all depressed patients, nonresponders are characterized by impaired GABA-ergic signaling and the simultaneous presence of the inflammatory component. Pharmacological agents able to curb pathological immune responses and modulate ineffective GABA-ergic neurotransmission are thought to improve therapeutic outcomes in the treatment-resistant subgroup of depressed patients. Here, we report on a set of dually acting molecules designed to simultaneously modulate GABA-A and 5-HT6 receptor activity. The serotonin 5-HT6 receptor was chosen as a complementary molecular target, due to its promising antidepressant-like activities reported in animal studies. Within the study we identified that lead molecule 16 showed a desirable receptor profile and physicochemical properties. In pharmacological studies, 16 was able to reduce the secretion of proinflammatory cytokines and decrease oxidative stress markers. In animal studies, 16 exerted antidepressant-like activity deriving from a synergic interplay between 5-HT6 and GABA-A receptors. Altogether, the presented findings point to hybrid 16 as an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.

The effects of masupirdine on the neuropsychiatric symptoms were explored.
Masupirdine (SUVN-502) was evaluated for its effects on cognition in patients with moderate AD. The prespecified primary outcome showed no drug-placebo difference. Post hoc analyses of domains of the 12-item neuropsychiatric inventory scale were carried out.
In a subgroup of patients (placebo, n = 57; masupirdine 50 mg, n = 53; masupirdine 100 mg, n = 48) with baseline agitation/aggression symptoms ≥1, a statistically significant reduction in agitation/aggression scores was observed in masupirdine 50 mg (95% confidence interval (CI), -1.9 to -0.5, p < 0.001) and masupirdine 100 mg (95% CI, -1.7 to -0.3, p = 0.007) treated arms at Week 13 in comparison to placebo and the effect was sustained for trial duration of 26 weeks in the masupirdine 50 mg treatment arm (95% CI, -2.3 to -0.8, p < 0.001). Similar observations were noted in the subgroup of patients (placebo, n = 29; masupirdine 50 mg, n = 30; masupirdine 100 mg, n = 21) with baseline agitation/aggression symptoms ≥3. In the subgroup of patients (placebo, n = 28; masupirdine 50 mg, n = 28; masupirdine 100 mg, n = 28) who had baseline psychosis symptoms and/or symptom emergence, a significant reduction in psychosis scores was observed in the masupirdine 50 mg (Week 4: 95% CI, -2.8 to -1.4, p < 0.001; Week 13: 95% CI, -3.3 to -1.3, p < 0.001) and masupirdine 100 mg (Week 4: 95% CI, -1.4 to 0, p = 0.046; Week 13: 95% CI, -1.9 to 0.1, p = 0.073) treatment arms in comparison to placebo.
Further research is warranted to explore the potential beneficial effects of masupirdine on NPS.

BACKGROUND: Alzheimer\'s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognition, memory and activities of daily living. Selective blockade of serotonin-6 (5-HT6) receptors, which are exclusively localized to the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5-HT6 receptor antagonist with pro-cognitive properties in animal models of cognition.
METHODS: The efficacy and safety of masupirdine were evaluated in patients with moderate AD concurrently treated with donepezil and memantine. A total of 564 patients were randomized in a 1:1:1 ratio. The study consisted of a 26-week double-blind treatment period. The primary efficacy outcome was the 11-item cognitive subscale of the Alzheimer\'s Disease Assessment Scale (ADAS-Cog 11). Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). In exploratory post hoc analyses, patients were subdivided based on the use of memantine dosage forms and memantine plasma concentrations, to evaluate the impact of memantine on the efficacy of masupirdine.
RESULTS: In an exploratory post hoc analysis, less worsening in cognition (ADAS-Cog 11 scores) was observed with masupirdine treatment as compared with placebo in patients whose trough memantine plasma concentrations were ≤ 100 ng/mL.
CONCLUSIONS: Although prespecified study endpoints of the phase 2 study were not met, these exploratory post hoc subgroup observations are hypothesis-generating and suggest that the efficacy of masupirdine was adversely affected by concurrent therapy with memantine. Further assessment of masupirdine to determine its potential role as a treatment option for cognitive deficits associated with AD is warranted.
BACKGROUND: The study was registered at ClinicalTrials.gov (NCT02580305).

Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT6 receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT6 receptors contribute to increased mTOR activity in the brain of Nf1+/- mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT6 receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1+/- mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT6 receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT6 receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients.

A new series of twenty-two C-5 substituted N-arylsulfonylindoles was prepared with the aim of exploring the influence of C-5 substitution on 5-HT6 receptor affinity. Eleven compounds showed moderate to high affinity at the receptor (Ki = 58-403 nM), with compound 4d being identified as the most potent ligand. However, regarding C-5 substitution, both methoxy and fluorine were detrimental for receptor affinity compared to our previously published unsubstituted compounds. In order to shed light on these observations, we performed docking and molecular dynamics simulations with the most potent compounds of each series (4d and 4l) and PUC-10, a highly active ligand previously reported by our group. The comparison brings about deeper insight about the influence of the C-5 substitution on the binding mode of the ligands, suggesting that these replacements are detrimental to the affinity due to precluding a ligand from reaching deeper inside the binding site. Additionally, CoMFA/CoMSIA studies were performed to systematize the information of the main structural and physicochemical characteristics of the ligands, which are responsible for their biological activity. The CoMFA and CoMSIA models presented high values of q2 (0.653; 0.692) and r2 (0.879; 0.970), respectively. Although the biological activity of the ligands can be explained in terms of the steric and electronic properties, it depends mainly on the electronic nature.

Serotonin type 6 receptor (5-HT6R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6R. This modification has changed the compound\'s activity at 5-HT6R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT6R inverse agonists.

The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2-/-) are naturally highly aggressive, while heterozygous mice (Tph2+/-) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically \'susceptible\' heterozygous mice (Tph2+/-).
Tph2+/- male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied.
Stressed Tph2+/- mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/- mice.
Rescue experiments would help to verify causal relationships of reported changes.
The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes.

The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer\'s disease (AD) and associated disorders.
The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages.
Patients were classified according to the \"ABC\" NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD (\"High\"; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), \"Low\" (n = 18), \"Int\" (n = 20), and \"High\" (n = 15).
In vitro binding assays did not show significant differences for the KD and Bmax parameters between \"High\" and HC groups. In vitro quantitative autoradiography showed a significant difference between the \"High\" and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined (\"Low\", \"Intermediate\", and \"High\") (p = 0.011).
This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.

5-HT6 receptor (5-HT6R) is implicated in cognitive dysfunction, mood disorder, psychosis, and eating disorders. However, despite its significant role in regulating the brain functions, regulation of 5-HT6R at the molecular level is poorly understood. Here, using yeast two-hybrid assay, we found that human 5-HT6R directly binds to neuro-oncological ventral antigen 1 (Nova-1), a brain-enriched splicing regulator. The interaction between 5-HT6R and Nova-1 was confirmed using GST pull-down and co-immunoprecipitation assays in cell lines and rat brain. The splicing activity of Nova-1 was decreased upon overexpression of 5-HT6R, which was examined by detecting the spliced intermediates of gonadotropin-releasing hormone (GnRH), a known pre-mRNA target of Nova-1, using RT-PCR. In addition, overexpression of 5-HT6R induced the translocation of Nova-1 from the nucleus to cytoplasm, resulting in the reduced splicing activity of Nova-1. In contrast, overexpression of Nova-1 reduced the activity and the total protein levels of 5-HT6R. Taken together, these results indicate that when the expression levels of 5-HT6R or Nova-1 protein are not properly regulated, it may also deteriorate the function of the other.