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Modulators of orexin receptors are being developed for neurological illnesses such as sleep disorders, addictive behaviours and other psychiatric diseases. We herein describe the discovery of CVN766, a potent orexin 1 receptor antagonist that has greater than 1000-fold selectivity for the orexin 1 receptor over the orexin 2 receptor and demonstrates low off target hits in a diversity screen. In agreement with its in vitro ADME data, CVN766 demonstrated moderate in vivo clearance in rodents and displayed good brain permeability and target occupancy. This drug candidate is currently being investigated in clinical trials for schizophrenia and related psychiatric conditions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors were either full time employees of Takeda Cambridge or Cerevance Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C347 6.36b of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar D-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer's disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and D-serine increases following administration of low oral doses.

The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

N-methyl-d-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, d-serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of d-amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases d-serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications. [ABSTRACT FROM AUTHOR]

Schizophrenia is a chronic neuropsychiatric syndrome that significantly impacts daily function and quality of life. All of the available guidelines suggest a combined treatment approach with pharmacologic agents and psychological interventions. However, one in three patients is a non-responder, the effect on negative and cognitive symptoms is limited, and many drug-related adverse effects complicate clinical management. As a result, discovering novel drugs for schizophrenia presents a significant challenge for psychopharmacology. This selective review of the literature aims to outline the current knowledge on the aetiopathogenesis of schizophrenia and to present the recently approved and newly discovered pharmacological substances in treating schizophrenia. We discuss ten novel drugs, three of which have been approved by the FDA (Olanzapine/Samidorphan, Lumateperone, and Pimavanserin). The rest are under clinical trial investigation (Brilaroxazine, Xanomeline/Trospium, Emraclidine, Ulotaront, Sodium Benzoate, Luvadaxistat, and Iclepertin). However, additional basic and clinical research is required not only to improve our understanding of the neurobiology and the potential novel targets in the treatment of schizophrenia, but also to establish more effective therapeutical interventions for the syndrome, including the attenuation of negative and cognitive symptoms and avoiding dopamine blockade-related adverse effects. [ABSTRACT FROM AUTHOR]

The clinically used glitazones (rosiglitazone and pioglitazone) for type 2 diabetes mellitus therapy have been linked to serious side effects such as fluid retention, congestive heart failure, weight gain, bone loss, and an increased risk of bladder cancer. The complete activation of PPAR-γ receptors in target tissues is linked to these effects. Many studies have demonstrated that partial PPAR-γ activators (GW0072, PAT5A, GQ16) give equivalent therapeutic benefits to full PPAR-γ agonists without the associated side effects. These breakthroughs cleared the path for the development of partial agonists or selective PPAR-γ modulators (SPPARγMs). This study combined pharmacophore modeling, molecular docking, and an adipogenesis experiment to identify thiazolidine analogs as SPPARMs/partial agonists. A custom library of 220 molecules was created and virtual screened to discover 90 compounds as SPPARγMs/ partial agonists. The chosen eight compounds were synthesized and tested for adipogenesis using 3T3L1 cell lines. These compounds' partial agonistic activity was evaluated in 3T3L1 cell lines by comparing their capacity to stimulate PPAR-γ mediated adipogenesis to that of a full agonist, rosiglitazone. The findings of the adipogenesis experiment demonstrate that all eight compounds examined had a partial potential to stimulate adipogenesis when compared to the full agonist, rosiglitazone. The current investigation identified eight possible PPAR-γ partial agonists or SPPARγMs that may be effective in the treatment of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Paeoniflorin is a glycoside compound found in Paeonia lactiflora Pall that is used in traditional herbal medicine and shows various protective effects on the cardio-cerebral vascular system. It has been reported that the pharmacological effects of paeoniflorin might be generated by its metabolites. However, the bioavailability of paeoniflorin by oral administration is low, which greatly limits its clinical application. In this paper, a paeoniflorin-converting enzyme gene (G6046, GenBank accession numbers: OP856858) from Cunninghamella blakesleeana (AS 3.970) was identified by comparative analysis between MS analysis and transcriptomics. The expression, purification, enzyme activity, and structure of the conversion products produced by this paeoniflorin-converting enzyme were studied. The optimal conditions for the enzymatic activity were found to be pH 9, 45 °C, resulting in a specific enzyme activity of 14.56 U/mg. The products were separated and purified by high-performance counter-current chromatography (HPCCC). Two main components were isolated and identified, 2-amino-2-p-hydroxymethyl-methyl alcohol-benzoate (tirs-benzoate) and 1-benzoyloxy-2,3-propanediol (1-benzoyloxypropane-2,3-diol), via UPLC-Q-TOF-MS and NMR. Additionally, paeoniflorin demonstrated the ability to metabolize into benzoic acid via G6046 enzyme, which might exert antidepressant effects through the blood–brain barrier into the brain. [ABSTRACT FROM AUTHOR]

Impaired activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) by D-serine is linked to cognitive aging. Whether this deregulation may be used to initiate pharmacological strategies has yet to be considered. To this end, we performed electrophysiological extracellular recordings at CA3/CA1 synapses in hippocampal slices from young and aged mice. We show that 0.1 nM of the soluble N-terminal recombinant fragment of the secreted amyloid-protein precursor-α (sAPPα) added in the bath significantly increased NMDAR activation in aged but not adult mice without impacting basal synaptic transmission. In addition, sAPPα rescued the age-related deficit of theta-burst-induced long-term potentiation. Significant NMDAR improvement occurred in adult mice when sAPPα was raised to 1 nM, and this effect was drastically reduced in transgenic mice deprived of D-serine through genetic deletion of the synthesizing enzyme serine racemase. Altogether, these results emphasize the interest to consider sAPPα treatment targeting D-serine-dependent NMDAR deregulation to alleviate cognitive aging. [ABSTRACT FROM AUTHOR]

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Based on longitudinal research conducted with 21 Mexican immigrants between 2018 and 2021, this article examines the challenges the COVID‐19 pandemic posed to undocumented immigrants in the United States attempting to provide care for aging parents in Mexico. As the United States excluded undocumented immigrants from pandemic support, the pandemic undermined their ability to provide health care for their parents even as the Mexican public health care system crumbled. Meanwhile, as the pandemic hastened their parents' demise, it thwarted immigrants' ability to time returns to see their parents before they died. While scholars have amply documented how spatial disparities exacerbated the impact of the pandemic among marginalized groups, few have examined the temporal disruptions caused by the pandemic. This article suggests that the pandemic provoked particular distress by desynchronizing the temporalities of family life across borders and preventing immigrants' abilities to coordinate care for their parents in time. [COVID‐19, transnational families, eldercare, death, time] [ABSTRACT FROM AUTHOR]

Currently, due to the large number of reports regarding the harmfulness of food additives, more and more consumers follow the so-called "clean label" trend, i.e., prefer and choose the least-processed food products. One of the compounds known as a preservative with a high safety profile is sodium benzoate. While some studies show that it can be used to treat conditions such as depression, pain, schizophrenia, autism spectrum disorders, and neurodegenerative diseases, others report its harmfulness. For example, it was found to cause mutagenic effects, generate oxidative stress, disrupt hormones, and reduce fertility. Due to such disparate results, the purpose of this study is to comprehensively discuss the safety profile of sodium benzoate and its potential use in neurodegenerative diseases, especially in autism spectrum disorder (ASD), schizophrenia, major depressive disorder (MDD), and pain relief. [ABSTRACT FROM AUTHOR]

Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRN Vglut3 ) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRN Vglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRN Vglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRN Vglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders., (© 2022. The Author(s).)

A novel method has been developed for the synthesis of 6‐methoxy 2‐aroyl 3‐aryl benzofuran and benzothiophenes from 2‐(3‐Methoxy‐phenoxy or thioxy)‐1‐phenyl‐ethanone and substituted benzoyl chloride through Friedel–Crafts benzoylation and cyclization reaction. The method accepts a variety of functional groups on the benzoyl chloride. [ABSTRACT FROM AUTHOR]

Scalable and chromatography-free syntheses of chirally pure and orthogonally protected cis-3,4-diaminotetrahydrofurans prepared from a single starting material, 3,4-epoxytetrahydrofuran, are presented. [ABSTRACT FROM AUTHOR]

The vibro-acoustic characteristics of an automotive brake drum is studied by applying a hybrid approach, which combines a numerical vibration analysis with an analytical acoustic solution. Specifically, structural vibration of a drum is investigated with the numerical finite element analysis, and vibratory displacements of the outer surface of the drum is approximated by simple mathematical expressions. Then, radiation of sound from the drum vibration is calculated using well-known theoretical solutions based on the simplified modal displacements. Finally, the calculation results are compared with those obtained by full numerical analyses. The results show that the numerical-analytical hybrid method allows relatively accurate calculation of vibro-acoustic properties of a brake drum under realistic boundary conditions. [ABSTRACT FROM AUTHOR]

The article presents abstracts on geriatrics research, which include screening tools for cognitive impairment and depression in older patients, frailty screening in older surgical inpatients, and end-of-life care in Parkinson's disease.

An one-pot-reaction methodology was developed to synthesize a variety of polysubstituted 3-aryl-2-arylmethylene amino- 4-hydroxybenzofurans from substituted β-nitrostyrenes, aromatic aldehydes, ammonium acetate, and cyclohexane-1,3-diones for the generation of a wide range of structurally interesting and pharmacologically significant compounds. The reaction pathway involves Michael addition of substituted nitrostyrenes and cyclohexane-1,3- diones, then nucleophilic addition of 2-(2-nitro-1-phenylethyl)cyclohexane- 1,3-dione and Schiff base generated from aromatic aldehyde and ammonium acetate and intramolecular cyclization, followed by dehydroaromatization to afford the corresponding 3- aryl-2-arylmethyleneamino-4-hydroxybenzofurans. [ABSTRACT FROM AUTHOR]

Tactical voting is generally understood through a rational choice framework, if only because no other theory predicts tactical voting. In formal rational choice models voters are assumed to be short-term instrumentally rational and those for whom it is utility-maximizing to vote for a party other than the preferred party are said to be tactical voters. Since no one fulfils the abstract conception of a short-term instrumentally rational voter in real life, tactical voters should be identified by their predominant motivations and behaviour conforming to rational choice specifications.

Focuses on the modeling of spatial allocation of resources over constituencies as an optimization problem in which governing parties face uncertainty about voter preferences but seek their chances of getting re-elected. Need for a rational government to allocate extra resources to marginal constituencies; Underlying assumptions in the model.

Understanding the genetic factors of obesity requires consideration of the genetic basis of the underlying etiological factors including energy expenditure and substrate utilization. Genetic susceptibility studies suggest that altered energy expenditure and/or preferential substrate utilization are likely to be involved in the etiology of obesity. Twin and family studies suggest that there is a strongly heritable component to resting energy expenditure, substrate utilization, and the thermic response to feeding. Physical activity energy expenditure has been less well studied; new data are presented in young sib pairs that suggest moderate heritability of nonresting energy expenditure. Only a few candidate gene studies have been performed to examine the role of basic proteins involved in energy expenditure (the sodium–potassium ATPase and the uncoupling protein) or substrate utilization (fatty acid binding protein). The lack of information in this area warrants further investigation into genetic aspects of energy and substrate metabolism. [ABSTRACT FROM AUTHOR]

Analyzes the components of constituency activism in general elections in Great Britain, in relation to campaigning and advertising. Details on expenditure reported by parties on the campaigns in each constituency; Reference to a study of local campaigns at the 1992 general election; Assessment of Labour Party spending in the 1987 general election.

Explores the relationship between local campaigning and tactical voting in England, at the 1992 general election. Evidence of partisan dealignment; Effect of local campaign efforts on constituency results.

Metabolic syndrome (MetS) is a highly prevalent disease cluster worldwide. It requires polypharmacological treatment of the single conditions including type II diabetes, hypertension, and dyslipidemia, as well as the associated comorbidities. The complex treatment regimens with various drugs lead to drug-drug interactions and inadequate patient adherence, resulting in poor management of the disease. Multi-target approaches aim at reducing the polypharmacology and improving the efficacy. This review summarizes the medicinal chemistry efforts to develop multi-target ligands for MetS. Different combinations of pharmacological targets in context of in vivo efficacy and future perspective for multi-target drugs in MetS are discussed. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. The number of AD cases has been rapidly growing worldwide. Several the related etiological hypotheses include atypical amyloid β (Aβ) deposition, neurofibrillary tangles of tau proteins inside neurons, disturbed neurotransmission, inflammation, and oxidative stress. During AD progression, aberrations in neurotransmission cause cognitive decline—the main symptom of AD. Here, we review the aberrant neurotransmission systems, including cholinergic, adrenergic, and glutamatergic network, and the interactions among these systems as they pertain to AD. We also discuss the key role of N-methyl-d-aspartate receptor (NMDAR) dysfunction in AD-associated cognitive impairment. Furthermore, we summarize the results of recent studies indicating that increasing glutamatergic neurotransmission through the alteration of NMDARs shows potential for treating cognitive decline in mild cognitive impairment or early stage AD. Future studies on the long-term efficiency of NMDA-enhancing strategies in the treatment of AD are warranted. [ABSTRACT FROM AUTHOR]

Background: An increasing number of studies have shown that the brain–gut–microbiota axis may significantly contribute to Alzheimer's disease (AD) pathogenesis. Moreover, impaired memory and learning involve the dysfunction neurotransmission of glutamate, the agonist of the N-methyl-d-aspartate receptor and a major excitatory neurotransmitter in the brain. This systematic review aimed to summarize the current cutting-edge research on the gut microbiota and glutamate alterations associated with dementia. Methods: PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials, and Cochrane Systematic Reviews were reviewed for all studies on glutamate and gut microbiota in dementia published up until Feb 2020. Results: Several pilot studies have reported alterations of gut microbiota and metabolites in AD patients and other forms of dementia. Gut microbiota including Bacteroides vulgatus and Campylobacter jejuni affect glutamate metabolism and decrease the glutamate metabolite 2-keto-glutaramic acid. Meanwhile, gut bacteria with glutamate racemase including Corynebacterium glutamicum, Brevibacterium lactofermentum, and Brevibacterium avium can convert l-glutamate to d-glutamate. N-methyl-d-aspartate glutamate receptor (NMDAR)-enhancing agents have been found to potentially improve cognition in AD or Parkinson's disease patients. These findings suggest that d-glutamate (d-form glutamate) metabolized by the gut bacteria may influence the glutamate NMDAR and cognitive function in dementia patients. Conclusions: Gut microbiota and glutamate are potential novel interventions to be developed for dementia. Exploring comprehensive cognitive functions in animal and human trials with glutamate-related NMDAR enhancers are warranted to examine d-glutamate signaling efficacy in gut microbiota in patients with AD and other neurodegenerative dementias. [ABSTRACT FROM AUTHOR]