Novel sigma 1-antagonists with -(+)-normetazocine scaffold: synthesis, molecular modeling, and antinociceptive effect.

Inflammatory pain represents one of the unmet clinical needs for patients, as conventional therapies cause several side effects. Recently, new targets involved in inflammatory pain modulation have been identified, including the sigma-1 receptor (σ1R). Selective σ1R antagonists have demonstrated analgesic efficacy in acute and chronic inflammatory pain models.

Design, Synthesis, and Evaluation of Novel (-)-cis-N-Normetazocine Derivatives: In Vitro and Molecular Modeling Insights.

Suitable structural modifications of the functional groups at N-substituent of (-)-cis-N-normetazocine nucleus modulate the affinity and activity profile of related ligands toward opioid receptors. Our research group has developed several compounds and the most interesting ligands, LP1 and LP2, exhibited a dual-target profile for mu-opioid receptor (MOR) and delta-opioid receptor (DOR). Recent structure-affinity relationship studies led to the discovery of novel LP2 analogs (compounds 1 and 2), which demonstrated high MOR affinity in the nanomolar range.

Ocular surface disease index in Graves' orbitopathy: a cross-sectional study.

Introduction: Graves' Orbitopathy (GO) is an autoimmune disorder characterized by inflammation of orbital tissues, leading to various ocular manifestations, including ocular surface disease. This cross-sectional study aimed to assess the presence of ocular surface disease using the Ocular Surface Disease Index (OSDI) in patients with Graves' disease (GD) and moderate-to-severe active GO compared to those with GD and mild non-active GO. Additionally, we aimed to investigate the correlation between ocular surface disease and the eye features of GO.

Antagonism of BST2/Tetherin, a new restriction factor of respiratory syncytial virus, requires the viral NS1 protein.

Human respiratory syncytial virus (RSV) is an enveloped RNA virus and the leading viral agent responsible for severe pediatric respiratory infections worldwide. Identification of cellular factors able to restrict viral infection is one of the key strategies used to design new drugs against infection. Here, we report for the first time that the cellular protein BST2/Tetherin (a widely known host antiviral molecule) behaves as a restriction factor of RSV infection.

Development of selective sigma-1 receptor ligands with antiallodynic activity: A focus on piperidine and piperazine scaffolds.

The design and synthesis of a series of piperidine and piperazine-based derivatives as selective sigma receptor (SR) ligands associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose features. The most promising compounds were subjected to in vitro toxicity testing and subsequently screened for in vivo analgesic properties.

Comparison of the diagnostic accuracy of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society and American Association of Electrodiagnostic Medicine diagnostic criteria for multifocal motor neuropathy.

Background And Purpose: This study was undertaken to compare the sensitivity and specificity of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria for multifocal motor neuropathy (MMN) with those of the American Association of Electrodiagnostic Medicine (AAEM).

Methods: Sensitivity and specificity of the two sets of criteria were retrospectively evaluated in 53 patients with MMN and 280 controls with axonal peripheral neuropathy, inflammatory demyelinating polyneuropathy, or amyotrophic lateral sclerosis. Comparison of the utility of nerve conduction studies with different numbers of nerves examined was also assessed.

Two-Step Synthesis of Enantiomerically Pure Morphans from (R)-Carvone.

Enantiomerically pure 4-hydroxymorphan-7-ones were prepared in two steps from the natural product (R)-carvone. At first, the isopropenyl moiety of (R)-carvone was converted into the epoxide 7. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the α,β-unsaturated ketone established the morphan scaffold.

Exploring Structural Requirements for Sigma-1 Receptor Linear Ligands: Experimental and Computational Approaches.

Sigma-1 receptor (S1R) is involved in a large array of biological functions due to its ability to interact with various proteins and ion channels. Crystal structures of human S1R revealed the trimeric organization for which each protomer comprises the ligand binding pocket. This study applied a multistep computational procedure to develop a pharmacophore model obtained from molecular dynamics simulations of available cocrystal structures of well-known S1R ligands.

Design, Synthesis, and Cytotoxic Assessment of New Haloperidol Analogues as Potential Anticancer Compounds Targeting Sigma Receptors.

Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach.

Pediatric Migraine and Visual Cortical Excitability: A Prospective Observational Study with Sound-Induced Flash Illusions.

The pathophysiological mechanisms underlying migraine are more difficult to investigate in children than in the adult population. Abnormal cortical excitability turns out to be one of the most peculiar aspects of migraine, accounting for the manifestations of migraine attacks. Recently, visual cortical excitability has been explored effectively in adult migraineurs with a technique based on cross-modal audio-visual illusions (with sound-induced flash illusions (SIFIs) being reduced in migraineurs compared to non-migraineur subjects).

Retinal and Cortical Visual Processing Dysfunction in a Case of Mild Cognitive Impairment with Lewy Bodies: A Case Report.

The prodromal stage of Lewy body dementia includes a mild cognitive impairment with visual processing and/or attention-executive deficits. A clinical presentation with progressive visual loss is indeed seldom reported and can be misleading with a posterior cortical atrophy disease. While the neurodegeneration at the occipital cortex can only partially explain the visual disturbances of Lewy body dementia, more recently a retinal dysfunction has been suggested by preliminary optical coherence tomography and autoptic findings.

Assessment of diagnostic criteria for multifocal motor neuropathy in patients included in the Italian database.

Background And Purpose: This study aimed to assess the diagnostic criteria, ancillary investigations and treatment response using real-life data in multifocal motor neuropathy (MMN) patients.

Methods: Clinical and laboratory data were collected from 110 patients enrolled in the Italian MMN database through a structured questionnaire. Twenty-six patients were excluded due to the unavailability of nerve conduction studies or the presence of clinical signs and symptoms and electrodiagnostic abnormalities inconsistent with the MMN diagnosis.

Neurophysiological Alterations of the Visual Pathway in Posterior Cortical Atrophy: Systematic Review and a Case Series.

Background: The clinical features of posterior cortical atrophy (PCA), a rare condition often caused by Alzheimer's disease, have been recently defined, while little is known about its neurophysiological correlates.

Objective: To describe neurophysiological alterations of the visual pathway as assessed using visual field test (VF), visual evoked potentials (VEP), and electroretinogram (ERG) in PCA patients.

Methods: Studies reporting VF, VEPs, and ERG in PCA patients were selected according PRISMA method.

Designing drugs optimized for both blood-brain barrier permeation and intra-cerebral partition.

Introduction: With the increasing incidence and prevalence of neurological disorders globally, there is a paramount need for new pharmacotherapies. BBB effectively protects the brain but raises a profound challenge to drug permeation, with less than 2% of most drugs reaching the CNS.

Areas Covered: This article reviews aspects of the most recent design strategies, providing insights into ideas and concepts in CNS drug discovery.

IgG4 serum levels in Graves' orbitopathy.

Objective: IgG4-related disease (IgG4-RD) can involve many organs, including thyroid and orbital tissues. A link between IgG4, Graves' disease (GD) and Graves' orbitopathy (GO) has been proposed, but results are conflicting. Here we investigated the possible association between IgG4 and GO.

Statins in Graves Orbitopathy: A New Therapeutic Tool.

Purpose: Graves orbitopathy (GO) is the most common extrathyroidal manifestation of Graves disease. Although its pathogenesis is not fully elucidated, GO is commonly considered an autoimmune disease due to loss of self-tolerance against autoantigens shared by thyroid epithelial cells and orbital fibroblasts. High-dose intravenous glucocorticoids (ivGCs) are the most used treatment for moderate-to-severe, active GO, but the addition of other immunomodulating treatments can improve the efficacy of ivGCs.

Serum Neurofilament Light Chain in Replication Factor Complex Subunit 1 CANVAS and Disease Spectrum.

Background: Biallelic intronic AAGGG repeat expansions in the replication factor complex subunit 1 (RFC1) gene were identified as the leading cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome. Patients exhibit significant clinical heterogeneity and variable disease course, but no potential biomarker has been identified to date.

Objectives: In this multicenter cross-sectional study, we aimed to evaluate neurofilament light (NfL) chain serum levels in a cohort of RFC1 disease patients and to correlate NfL serum concentrations with clinical phenotype and disease severity.

Repetitive Transcranial Magnetic Stimulation of the Human Motor Cortex Modulates Processing of Heat Pain Sensation as Assessed by the Offset Analgesia Paradigm.

Offset analgesia (OA), which is defined as a disproportionately large reduction in pain perception following a small decrease in a heat stimulus, quantifies temporal aspects of endogenous pain modulation. In this study on healthy subjects, we aimed to (i) determine the Heat Pain Threshold (HPT) and the response to constant and dynamic heat stimuli assessing sensitization, adaptation and OA phenomena at the thenar eminence; (ii) evaluate the effects of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) of the primary motor cortex (M1) on these measures. Twenty-four healthy subjects underwent quantitative sensory testing before and after active or sham 10 Hz rTMS (1200 stimuli) of the left M1, during separate sessions.