Search

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. [ABSTRACT FROM AUTHOR]

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 N-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 (−)-cis-N-normetazocine skeleton. In radioligand binding assays, compounds 3 and 7 were found to display nanomolar binding affinity for the μ opioid receptor (MOR) (Ki = 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound 3 showed an antagonist effect against DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), a highly selective MOR prototype agonist, whereas compound 7 produced naloxone reversible effect at MOR. Moreover, compound 7, 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. [ABSTRACT FROM AUTHOR]

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 (5d and 5i) 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. [ABSTRACT FROM AUTHOR]

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 (σ1R) antagonism, could be an opioid adjuvant strategy. The in vitro σ1R and σ2R profiles of previous synthesized MOR/DOR agonists (−)-2R/S-LP2 (1), (−)-2R-LP2 (2), and (−)-2S-LP2 (3) were assayed. To investigate the pivotal role of N-normetazocine stereochemistry, we also synthesized the (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) compounds. (−)-2R/S-LP2 (1), (−)-2R-LP2 (2), and (−)-2S-LP2 (3) compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) 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. (−)-2S-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2R/S-LP2 (7), 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 N-normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin. [ABSTRACT FROM AUTHOR]

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1–4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents. [ABSTRACT FROM AUTHOR]

Ibogaine is a psychoactive indole alkaloid with high affinity for several targets including the σ2 receptor. Indeed, extensive data support the involvement of the σ2 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 σ2 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 σ2 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 σ2 pKi values of the new compounds, whereas a molecular docking study conducted upon the σ2 receptor built by homology modeling was used to further validate the best-scored molecules. We eventually evaluated pinoline, a carboline derivative, for σ2 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 σ2 receptor binding capabilities. [ABSTRACT FROM AUTHOR]

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 N -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 (-)- cis - N -normetazocine skeleton. In radioligand binding assays, compounds 3 and 7 were found to display nanomolar binding affinity for the μ opioid receptor (MOR) (K i = 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound 3 showed an antagonist effect against DAMGO ([D-Ala 2 , N-MePhe 4 , Gly-ol]-enkephalin), a highly selective MOR prototype agonist, whereas compound 7 produced naloxone reversible effect at MOR. Moreover, compound 7 , 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.