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. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC50 values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs.
The aim of this review is to summarize the effects of various naturally occurring polyphenols in the management of metabolic dysfunctions. This cluster of metabolic abnormalities comprises insulin ...resistance, increased levels of free fatty acids, hypercholesterolemia, obesity, hyperglycemia and hypertension, diabetes mellitus (DM) type 1 (T1DM) and type 2 (T2DM) along with DM-induced complications. Most of them are included in the well-known metabolic syndrome (MS). These metabolic dysfunctions in turn are tightly associated to a high risk of development of cardiovascular diseases. Although molecular mechanisms underlying the onset of metabolic dysfunctions and related complications are not yet clear, it is widely recognized that they are associated to oxidative stress and chronic low-grade of inflammatory levels.
We undertook a structured search of bibliographic references through the use of SciFinder. The database was provided by a division of ACS (American Chemical Society) and guarantees access to the world's most extensive and authoritative source of references. The search was performed using "heme oxygenase-1" as research topic and a subsequent refinement was done by using inclusion/exclusion criteria. The quality of retrieved papers was evaluated on the basis of standard tools.
From a careful review of the selected literature, of interest, the use of natural antioxidant polyphenols seems to be the ideal pharmacological treatment since they are endowed with strong antioxidant and anti-inflammatory properties. In particular, some polyphenols such as curcumin, quercetin, genistein, and caffeic acid phenethyl ester are able to potently activate nuclear factor erythroid 2-related factor 2 (Nrf2) and related downstream expression of enzymes such as heme oxygenase-1 (HO-1). Indeed, an overexpression of HO-1 has been demonstrated to play a beneficial role in metabolic diseases.
The following review is intended to stimulate interest in the role of natural occurring HO-1 inducers in metabolic dysfunction, focusing on the clinical potential of HO-1 activity to restore the balance between pro-oxidant and anti-oxidants systems.
Sigma receptors are a fascinating receptor protein class whose ligands are actually under clinical evaluation for the modulation of opioid analgesia and their use as positron emission tomography ...radiotracers. In particular, peculiar biological and therapeutic functions are associated with the sigma-2 (σ₂) receptor. The
₂ receptor ligands determine tumor cell death through apoptotic and non-apoptotic pathways, and the overexpression of
₂ receptors in several tumor cell lines has been well documented, with significantly higher levels in proliferating tumor cells compared to quiescent ones. This acknowledged feature has found practical application in the development of cancer cell tracers and for ligand-targeting therapy. In this context, the development of new ligands that target the
₂ receptors is beneficial for those diseases in which this protein is involved. In this paper, we conducted a search of new potential
₂ receptor ligands among a database of 1517 "small" marine natural products constructed by the union of the Seaweed Metabolite and the Chemical Entities of Biological Interest (ChEBI) Databases. The structures were passed through two filters that were constituted by our developed two-dimensional (2D) and three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) statistical models, and successively docked upon a
₂ receptor homology model that we built according to the FASTA sequence of the
₂/TMEM97 (SGMR2_HUMAN) receptor.
Neurodegeneration is a slow and progressive loss of neuronal cells or their function in specific regions of the brain or in the peripheral system. Among several causes responsible for the most common ...neurodegenerative diseases (NDDs), cholinergic/dopaminergic pathways, but also some endogenous receptors, are often involved. In this context, sigma 1 receptor (S1R) modulators can be used as neuroprotective and antiamnesic agents. Herein, we describe the identification of novel S1R ligands endowed with antioxidant properties, potentially useful as neuroprotective agents. We also computationally assessed how the most promising compounds might interact with the S1R protein's binding sites. The in silico predicted ADME properties suggested that they could be able to cross the brain-blood-barrier (BBB), and to reach the targets. Finally, the observation that at least two novel ifenprodil analogues (
and
) induce an increase of the mRNA levels of the antioxidant NRF2 and SOD1 genes in SH-SY5Y cells suggests that they might be effective agents for protecting neurons against oxidative damage.
Chronic neuropathic pain emerges from either central or peripheral lesions inducing spontaneous or amplified responses to non-noxious stimuli. Despite different pharmacological approaches to treat ...such a chronic disease, neuropathic pain still represents an unmet clinical need, due to long-term therapeutic regimens and severe side effects that limit application of currently available drugs. A critical phenomenon involved in central sensitization is the exchange of signalling molecules and cytokines, between glia and neurons, driving the chronicization process. Herein, using a chronic constriction injury (CCI) model of neuropathic pain, we evaluated the efficacy of the mu (M-) and delta (D-) opioid receptor (-OR) targeting agent LP2 in modulating connexin-based heterocellular coupling and cytokine levels. We found that long-term efficacy of LP2 is consequent to MOR-DOR targeting resulting in the reduction of CCI-induced astrocyte-to-microglia heterocellular coupling mediated by connexin 43. We also found that single targeting of DOR reduces TNF and IL-6 levels in the chronic phase of the disease, but the peripheral and central discharge as the primary source of excitotoxic stimulation in the spinal cord requires a simultaneous MOR-DOR targeting to reduce CCI-induced neuropathic pain.
Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics ...endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σ
R) antagonism, could be an opioid adjuvant strategy. The in vitro σ
R and σ
R profiles of previous synthesized MOR/DOR agonists (-)-2
/
-LP2 (
), (-)-2
-LP2 (
), and (-)-2
-LP2 (
) were assayed. To investigate the pivotal role of
-normetazocine stereochemistry, we also synthesized the (+)-2
/
-LP2 (
), (+)-2
-LP2 (
), and (+)-2
-LP2 (
) compounds. (-)-2
/
-LP2 (
), (-)-2
-LP2 (
), and (-)-2
-LP2 (
) compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2
/
-LP2 (
), (+)-2
-LP2 (
), and (+)-2
-LP2 (
) isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (-)-2
-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2
/
-LP2 (
), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed
-normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.
Over-regulation of Heme oxygenase 1 (HO-1) has been recently identified in many types of human cancer, and in these cases, poor clinical outcomes are normally reported. Indeed, the inhibition of HO-1 ...is being considered as an anticancer approach. Imidazole scaffold is normally present in most of the classical HO-1 inhibitors and seems indispensable to the inhibitory activity due to its strong interaction with the Fe(II) of the heme group. In this paper, we searched for new potentially HO-1 inhibitors among three different databases: Marine Natural Products (MNP), ZINC Natural Products (ZNP) and Super Natural II (SN2). 484,527 compounds were retrieved from the databases and filtered through four statistical/computational filters (2D descriptors, 2D-QSAR pharmacophoric model, 3D-QSAR pharmacophoric model, and docking). Different imidazole-based compounds were suggested by our methodology to be potentially active in inhibiting the HO-1, and the results have been rationalized by the bioactivity of the filtered molecules reported in the literature.
In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate compounds with improved analgesia. ...To do that, the phenyl ring in the
-substituent of our lead compound LP1 was replaced by an electron-rich or electron-deficient ring and linked through a propanamide or butyramide spacer at the basic nitrogen of the (-)-
-
-normetazocine skeleton. In radioligand binding assays, compounds
and
were found to display nanomolar binding affinity for the μ opioid receptor (MOR) (K
= 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound
showed an antagonist effect against DAMGO (D-Ala
, N-MePhe
, Gly-ol-enkephalin), a highly selective MOR prototype agonist, whereas compound
produced naloxone reversible effect at MOR. Moreover, compound
, as potent as LP1 and DAMGO at MOR, was able to reduce thermal and inflammatory pain assessed by the mouse tail-flick test and rat paw pressure thresholds (PPTs) measured by a Randall-Selitto test.
(±)-MRJF22 (±)-2, a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) ...via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viability in a comparable manner to bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration, and tube formation in vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.
Ibogaine is a psychoactive indole alkaloid with high affinity for several targets including the
₂ receptor. Indeed, extensive data support the involvement of the
₂ receptor in neurological disorders, ...including Alzheimer's disease, schizophrenia, alcohol abuse and pain. Due to its serious side effects which prevent ibogaine from potential clinical applications, novel ibogaine derivatives endowed with improved
₂ receptor affinity may be particularly beneficial. With the purpose to facilitate the investigation of iboga alkaloid derivatives which may serve as templates for the design of selective
₂ receptor ligands, here we report a deconstruction study on the ibogaine tricyclic moiety and a successive scaffold-hopping of the indole counterpart. A 3D-QSAR model has been applied to predict the
₂ p
values of the new compounds, whereas a molecular docking study conducted upon the
₂ receptor built by homology modeling was used to further validate the best-scored molecules. We eventually evaluated pinoline, a carboline derivative, for
₂ receptor affinity through radioligand binding assay and the results confirmed the predicted high µM range of affinity and good selectivity. The obtained results could be helpful in the drug design process of new ibogaine simplified analogs with improved
₂ receptor binding capabilities.
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