Inflammaging and Immunosenescence in the Post-COVID Era: Small Molecules, Big Challenges.

Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so-called long-COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self-sustaining process.

Alterations of synaptic plasticity in Angelman syndrome model mice are rescued by 5-HT7R stimulation.

Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by motor disfunction, seizures, intellectual disability, speech deficits, and autism-like behavior, showing high comorbidity with Autism Spectrum Disorders (ASD). It is known that stimulation of the serotonin receptor 7 (5-HT7R) can rescue some of the behavioral and neuroplasticity dysfunctions in animal models of Fragile X and Rett syndrome, two pathologies associated with ASD. In view of these observations, we hypothesised that alterations of 5-HT7R signalling might also be involved in AS.

Multitarget-Directed Ligands Hitting Serotonin Receptors: A Medicinal Chemistry Survey.

Serotonin (5-hydroxytryptamine, 5-HT) is a ubiquitous neurotransmitter in the human body. In the central nervous system, 5-HT affects sleep, pain, mood, appetite, and attention, while in the peripheral nervous system, 5-HT modulates peristalsis, mucus production, and blood vessel dilation. Fourteen membrane receptors mediate 5-HT activity.

Allosteric Modulators of Serotonin Receptors: A Medicinal Chemistry Survey.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter regulating numerous physiological functions, and its dysregulation is a crucial component of the pathological processes of schizophrenia, depression, migraines, and obesity. 5-HT interacts with 14 different receptors, of which 5-HTRs, 5-HTRs, and 5-HTRs are G protein-coupled receptors (GPCRs), while 5-HTR is a ligand-gated ion channel. Over the years, selective orthosteric ligands have been identified for almost all serotonin receptors, yielding several clinically relevant drugs.

Modulation of neuronal morphology by antipsychotic drug: Involvement of serotonin receptor 7.

Antipsychotic drugs (APDs) are the primary pharmacological treatment for schizophrenia, a complex disorder characterized by altered neuronal connectivity. Atypical or second-generation antipsychotics, such as Risperidone (RSP) and Clozapine (CZP) predominantly block dopaminergic D and serotonin receptor 2A (5-HT2A) neurotransmission. Both compounds also exhibit affinity for the 5-HT7R, with RSP acting as an antagonist and CZP as an inverse agonist.

Microglia Depletion Attenuates the Pro-Resolving Activity of the Formyl Peptide Receptor 2 Agonist AMS21 Related to Inhibition of Inflammasome NLRP3 Signalling Pathway: A Study of Organotypic Hippocampal Cultures.

Microglial cells have been demonstrated to be significant resident immune cells that maintain homeostasis under physiological conditions. However, prolonged or excessive microglial activation leads to disturbances in the resolution of inflammation (RoI). Formyl peptide receptor 2 (FPR2) is a crucial player in the RoI, interacting with various ligands to induce distinct conformational changes and, consequently, diverse biological effects.

Development of potent isoflavone-based formyl peptide receptor 1 (FPR1) antagonists and their effects in gastric cancer cell models.

Formyl peptide receptor-1 (FPR1) is a G protein-coupled chemoattractant receptor that plays a crucial role in the trafficking of leukocytes into the sites of bacterial infection and inflammation. Recently, FPR1 was shown to be expressed in different types of tumor cells and could play a significant role in tumor growth and invasiveness. Starting from the previously reported FPR1 antagonist 4, we have designed a new series of 4H-chromen-2-one derivatives that exhibited a substantial increase in FPR1 antagonist potency.

Stimulation of Formyl Peptide Receptor-2 by the New Agonist CMC23 Protects against Endotoxin-Induced Neuroinflammatory Response: A Study in Organotypic Hippocampal Cultures.

A substantial body of evidence demonstrates an association between a malfunction in the resolution of acute inflammation and the development of chronic inflammation. Recently, in this context, the importance of formyl peptide receptor 2 (FPR2) has been underlined. FPR2 activity is modulated by a wide range of endogenous ligands, including specialized pro-resolving mediators (SPMs) (e.

Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and -KO mouse models.

Introduction: Autism spectrum disorder (ASD) is a persistent neurodevelopmental condition characterized by two core behavioral symptoms: impaired social communication and interaction, as well as stereotypic, repetitive behavior. No distinct cause of ASD is known so far; however, excitatory/inhibitory imbalance and a disturbed serotoninergic transmission have been identified as prominent candidates responsible for ASD etiology.

Methods: The GABA receptor agonist R-Baclofen and the selective agonist for the 5HT serotonin receptor LP-211 have been reported to correct social deficits and repetitive behaviors in mouse models of ASD.

Structure-Activity Relationships and Therapeutic Potential of Purinergic P2X7 Receptor Antagonists.

The purinergic P2X7 receptor (P2X7R), an ATP-gated non-selective cation channel, has emerged as a gatekeeper of inflammation that controls the release of proinflammatory cytokines. As a key player in initiating the inflammatory signaling cascade, the P2X7 receptor is currently under intense scrutiny as a target for the treatment of different pathologies, including chronic inflammatory disorders (rheumatoid arthritis and osteoarthritis), chronic neuropathic pain, mood disorders (depression and anxiety), neurodegenerative diseases, ischemia, cancer (leukemia), and many others. For these reasons, pharmaceutical companies have invested in discovering compounds able to modulate the P2X7R and filed many patent applications.

5-HT Receptors Regulate Excitatory-Inhibitory Balance in Mouse Spinal Cord Dorsal Horn.

Serotonergic receptors of the 5-HT type (5-HTRs) are widely expressed in the central nervous system (CNS), where they modulate several functions, such as pain. Behavioral experiments have shown both anti- and pro-nociceptive actions of 5-HTRs, although an analgesic effect seems to be prevalent. In the spinal cord dorsal horn, the mechanisms involved in 5-HTR-mediated synaptic modulation are still poorly understood, especially those regarding the control of synaptic inhibition.

Design, Synthesis, and Characterization of a Novel Fluoroprobe for Live Human Islet Cell Imaging of Serotonin 5-HT Receptor.

Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5-HT receptor subtype found in pancreatic islets, serotonin receptor 1A (5-HT ) demonstrates a unique ability to inhibit β-cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT receptor.

Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Ureidopropanamides as Formyl Peptide Receptor 2 (FPR2) Agonists to Target the Resolution of Inflammation in Central Nervous System Disorders.

Formyl peptide receptor 2 (FPR2) agonists can boost the resolution of inflammation and can offer alternative approaches for the treatment of pathologies with underlying chronic neuroinflammation, including neurodegenerative disorders. Starting from the FPR2 agonist previously identified in our laboratory and through fine-tuning of FPR2 potency and metabolic stability, we have identified a new series of ureidopropanamide derivatives endowed with a balanced combination of such properties. Computational studies provided insights into the key interactions of the new compounds for FPR2 activation.

Behavioral, Anti-Inflammatory, and Neuroprotective Effects of a Novel FPR2 Agonist in Two Mouse Models of Autism.

Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental conditions characterized by social deficits, repetitive stereotyped behaviors, and altered inflammatory responses. Accordingly, children with ASD show decreased plasma levels of lipoxin A4 (LXA4), a mediator involved in the resolution of inflammation, which is the endogenous ligand of the formyl peptide receptor 2 (FPR2). To investigate the role of FPR2 in ASDs, we have used a new ureidopropanamide derivative able to activate the receptor, named MR-39.

Design and Synthesis of Arylpiperazine Serotonergic/Dopaminergic Ligands with Neuroprotective Properties.

Long-chain arylpiperazine scaffold is a versatile template to design central nervous system (CNS) drugs that target serotonin and dopamine receptors. Here we describe the synthesis and biological evaluation of ten new arylpiperazine derivatives designed to obtain an affinity profile at serotonin 5-HT, 5-HT, 5-HT receptor, and dopamine D receptor of prospective drugs to treat the core symptoms of autism spectrum disorder (ASD) or psychosis. Besides the structural features required for affinity at the target receptors, the new compounds incorporated structural fragments with antioxidant properties to counteract oxidative stress connected with ASD and psychosis.

In Vitro and In Silico Analysis of the Residence Time of Serotonin 5-HT Receptor Ligands with Arylpiperazine Structure: A Structure-Kinetics Relationship Study.

During the last decade, the kinetics of drug-target interaction has received increasing attention as an important pharmacological parameter in the drug development process. Several studies have suggested that the lipophilicity of a molecule can play an important role. To date, this aspect has been studied for several G protein-coupled receptors (GPCRs) ligands but not for the 5-HT receptor (5-HTR), a GPCR proposed as a valid therapeutic target in neurodevelopmental and neuropsychiatric disorders associated with abnormal neuronal connectivity.

Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways.

Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflammation (RoI). The importance of specialized pro-resolving lipid mediators (SPMs) in RoI has been highlighted. Among them, lipoxins (LXA4) and aspirin-triggered lipoxin A4 (AT-LXA4) mediate beneficial responses through the activation of N-formyl peptide receptor-2 (FPR2).

The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1-42)-Induced Neuroinflammation in Mouse Models of Alzheimer's Disease.

The major histopathological hallmarks of Alzheimer's disease (AD) include β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Aβ 1-42 (Aβ) has been shown to induce neurotoxicity and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of Aβ were shown to be mediated by interactions with several cell surface receptors, including the chemotactic G protein-coupled N-formyl peptide receptor 2 (FPR2).

σ Receptor and Its Role in Cancer with Focus on a MultiTarget Directed Ligand (MTDL) Approach.

Sigma-2 (σ) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ receptor, and many σ ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors.

The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Exhibits Anti-Inflammatory Activity in LPS-Stimulated Organotypic Hippocampal Cultures.

Accumulating evidence indicates a pivotal role for chronic inflammatory processes in the pathogenesis of neurodegenerative and psychiatric disorders. G protein-coupled formyl peptide receptor 2 (FPR2) mediates pro-inflammatory or anti-/pro-resolving effects upon stimulation with biased agonists. We aimed to evaluate the effects of a new FPR2 ureidopropanamide agonist, compound MR-39, on neuroinflammatory processes in organotypic hippocampal cultures (OHCs) derived from control (WT) and knockout FPR2-/- mice (KO) exposed to bacterial endotoxin (lipopolysaccharide; LPS).

Formyl peptide receptor 2, as an important target for ligands triggering the inflammatory response regulation: a link to brain pathology.

Formyl peptide receptors (FPRs) belong to the family of seven-transmembrane G protein-coupled receptors. Among them, FPR2 is a low affinity receptor for N-formyl peptides and is considered the most promiscuous member of FPRs. FPR2 is able to recognize a broad variety of endogenous or exogenous ligands, ranging from lipid to proteins and peptides, including non-formylated peptides.

Serotonin 5-HT7 receptors require cyclin-dependent kinase 5 to rescue hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome.

Fragile X Syndrome is a genetic form of intellectual disability associated with autism, epilepsy and mood disorders. Electrophysiology studies in Fmr1 knockout (KO) mice, a murine model of Fragile X Syndrome, have demonstrated alterations of synaptic plasticity, with exaggerated long-term depression induced by activation of metabotropic glutamate receptors (mGluR-LTD) in Fmr1 KO hippocampus. We have previously demonstrated that activation of serotonin 5-HT7 receptors reverses mGluR-LTD in the hippocampus of wild-type and Fmr1 KO mice, thus correcting a synaptic dysfunction typically observed in this disease model.

Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders characterized by core symptoms such as impaired social interaction and communication, repetitive and stereotyped behaviors, and restricted interests. To date, there are no effective treatments for these core symptoms. Several studies have shown that the brain serotonin (5-HT) neurotransmission system is altered in both ASD patients and animal models of the disease.

Stimulation of the Serotonin Receptor 7 Restores Brain Histone H3 Acetylation and MeCP2 Corepressor Protein Levels in a Female Mouse Model of Rett Syndrome.

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene, characterized by severe behavioral and physiological impairments for which no cure is available. The stimulation of serotonin receptor 7 (5-HT7R) with its selective agonist LP-211 (0.25 mg/kg/day for 7 days) was proved to rescue neurobehavioral alterations in a mouse model of RTT.