Exploring the reactivity of bicyclic α-iminophosphonates to access new imidazoline I receptor ligands.

Recent studies pointed out the modulation of imidazoline I receptors (I-IR) by selective ligands as a putative strategy to face neurodegenerative diseases. Foregoing the classical 2-imidazoline/imidazole-containing I-IR ligands, we report a family of bicyclic α-iminophosphonates endowed with high affinity and selectivity upon I-IR and we advanced a representative compound B06 in preclinical phases. In this paper, we describe the synthetic possibilities of bicyclic α-iminophosphonates by exploring its ambivalent reactivity, leading to unprecedented molecules that showed promising activities as I-IR ligands in human brain tissues and good BBB permeation capabilities.

Effects of Preoperative Quadruple Therapy for Helicobacter pylori on Bariatric Surgery Metabolic Outcomes.

Purpose: To assess the effects of Helicobacter pylori (HP) eradication with an omeprazole, clarithromycin, amoxicillin, and metronidazole (OCAM) regimen on the metabolic profile and weight loss 12 months after bariatric surgery (BS).

Methods: Retrospective analysis of a prospective cohort of patients with morbid obesity undergoing BS. HP presence was tested preoperatively by gastric biopsy and treated with OCAM when positive.

Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer's Disease.

Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer's disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I receptors (I-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature.

Design and Synthesis of AMPK Activators and GDF15 Inducers.

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, .

Sex differences in the antidepressant-like response and molecular events induced by the imidazoline-2 receptor agonist CR4056 in rats.

In searching for novel targets to design antidepressants, among the characterized imidazoline receptors (IR), I2 receptors are an innovative therapeutical approach since they are dysregulated in major depressive disorder and by classical antidepressant treatments. In fact, several I2 agonists have been characterized for their antidepressant-like potential, but the results in terms of efficacy were mixed and exclusively reported in male rodents. Since there are well-known sex differences in antidepressant-like efficacy, this study characterized the potential effects induced by two I2 drugs, CR4056 (i.

Heterocycle-Based Multicomponent Reactions in Drug Discovery: From Hit Finding to Rational Design.

In the context of the structural complexity necessary for a molecule to selectively display a therapeutical action and the requirements for suitable pharmacokinetics, a robust synthetic approach is essential. Typically, thousands of relatively similar compounds should be prepared along the drug discovery process. In this respect, heterocycle-based multicomponent reactions offer advantages over traditional stepwise sequences in terms of synthetic economy, as well as the fast access to chemsets to study the structure activity relationships, the fine tuning of properties, and the preparation of larger amounts for preclinical phases.

An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta Off-Target Mechanisms Resistant to Aging.

Imidazoline receptors (IR) are classified into three receptor subtypes (IR, IR, and IR) and previous studies showed that regulation of IR signaling has neuroprotective potential. In order to know if IR has a role in modulating vascular tone in health and disease, we evaluated the putative vasoactive effects of two recently synthesized IR ligands, diethyl (1RS,3aSR,6aSR)-5-(3-chloro-4-fluorophenyl)-4,6-dioxo-1-phenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole -1-phosphonate (B06) and diethyl [(1-(3-chloro-4-fluorobenzyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-imidazol-4-yl]phosphonate] (MCR5). Thoracic aortas from Oncins France 1 (3- to 4-months-old) and C57BL/6 (3- to 4- and 16- to 17-months-old mice) were mounted in tissue baths to measure isometric tension.

Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I Receptor Ligand B06.

The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I receptors (I-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors.

Benzofuranyl-2-imidazoles as imidazoline I receptor ligands for Alzheimer's disease.

Recent findings unveil the pharmacological modulation of imidazoline I receptors (I-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile.

Disease-modifying treatment with I imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: a comparative study with donepezil.

Background And Purpose: The development of effective therapeutic strategies against Alzheimer's disease (AD) remains a challenge. I imidazoline receptor ligands have a neuroprotective role in AD. Moreover, co-treatment of AChE inhibitors with neuroprotective agents have shown better effects on the prevention of dementia.

I imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway.

Brain aging and dementia are current problems that must be solved. The levels of imidazoline 2 receptors (I-IRs) are increased in the brain in Alzheimer's disease (AD) and other neurodegenerative diseases. We tested the action of the specific and selective I-IR ligand B06 in a mouse model of accelerated aging and AD, the senescence-accelerated mouse prone 8 (SAMP8) model.

Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I-Imidazoline Receptor Ligand MCR5.

Behavioural and psychological symptoms of dementia (BPSD), including fear-anxiety- and depressive-like behaviour, are present in Alzheimer's disease (AD), together with memory decline. I-imidazoline receptors (I-IRs) have been associated with neuropsychiatric and neurodegenerative disorders, further, I-IR ligands have demonstrated a neuroprotective role in the central nervous system (CNS). In this study, we assessed the effect of the I-IR ligand MCR5 on both cognitive and non-cognitive symptoms in the Senescence accelerated mice prone 8 (SAMP8) mouse model.

Bicyclic α-Iminophosphonates as High Affinity Imidazoline I Receptor Ligands for Alzheimer's Disease.

Imidazoline I receptors (I-IR), widely distributed in the CNS and altered in patients that suffer from neurodegenerative disorders, are orphans from a structural point of view, and new I-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a new family of bicyclic α-iminophosphonates endowed with relevant affinities for human brain I-IR. Acute treatment in mice with a selected compound significantly decreased Fas-associated protein with death domain (FADD) in the hippocampus, a key signaling mediator of neuroprotective actions.

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I Receptor Ligands in Female SAMP8 Mice.

As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I-Imidazoline receptors (I-IR) are widely distributed in the central nervous system, and dysregulation of I-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I-IR ligands potentially contribute to the delay of neurodegeneration.