Prolonged exposure of cultured cortical neurons to the residue 25-35 fragment of beta-amyloid protein, in the presence of dizocilpine, an antagonist of the N-methyl-D-aspartate receptor, and of 6,7-dinitroquinoxaline-2,3-dione, an antagonist of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors, resulted in the expression of the proapoptotic protein Bax and neuronal death. Beta-amyloid protein(25-35)-induced neuronal death was substantially attenuated by the sigma1 receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate. The neuroprotective action of 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate was mimicked by the sigma1 ligand methyl (1S,2R)-2-[1-adamantyl(methyl)amino]methyl-1-phenylcyclopropanecarboxylate and was antagonized by the sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride. These results suggest that sigma1 receptor agonists might function as neuroprotectant agents in Alzheimer's disease.

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J. Neurochem. (2009) 109, 744–754. Abstract Previous studies have reported that selective sigma‐1 agonists may improve cognitive abilities in experimental animals possibly via a cholinergic mechanism. However, the issue of a direct action on to sigma‐1 receptors in memory‐related brain areas has been much less investigated. The newly synthetised compound methyl(1R,2S/1S,2R)‐2‐[4‐hydroxy‐4‐phenylpiperidin‐1‐yl)methyl]‐1‐(4‐methylphenyl) cyclopropanecarboxylate [(±)‐PPCC] has recently been shown to possess high affinity for the sigma‐1 receptor where it specifically acts as an agonist. Here, the functional effects of (±)‐PPCC were investigated in rat models of mild or severe cognitive dysfunction based on a sub‐total (≤ 70–80%) or complete (≥ 90–95%) central cholinergic depletion induced by different doses of the selective immunotoxin 192 IgG‐saporin injected intraventricularly. At 5–6 weeks post‐surgery, the lesioned animals exhibited dose‐dependent deficits in reference memory, as assessed using the Morris water maze task, whereas working memory abilities, evaluated using the radial arm water maze task, appeared equally impaired in the two dose groups. Daily treatment with (±)‐PPCC significantly improved both reference and working memory performance in all lesioned animals but it did not affect intact or sham‐lesioned subjects. In a separate test, treatment with (±)‐PPCC reversed the learning deficits induced by the muscarinic receptor antagonist atropine sulphate in both control and mild‐lesioned rats. The effect was blocked in lesioned, but not normal animals by pre‐treatment with the sigma‐1 antagonist N‐[2‐(3,4‐dichlorophenyl)ethyl]‐N‐methyl‐2‐(dimethylamino)ethylamine. The results suggest that (±)‐PPCC may efficiently ameliorate perturbed cognitive abilities, and that these anti‐amnesic effects most probably occur via a direct interaction of the compound with sigma‐1 receptors.

Since their discovery as distinct receptor proteins, the specific physiopathological role of sigma receptors (σRs) has been deeply investigated. It has been reported that these proteins, classified into two subtypes indicated as σ 1 and σ 2 , might play a pivotal role in cancer growth, cell proliferation, and tumor aggressiveness. As a result, the development of selective σR ligands with potential antitumor properties attracted significant attention as an emerging theme in cancer research. This perspective deals with the recent advances of σR ligands as novel cytotoxic agents, covering articles published between 2010 and 2020. An up-to-date description of the medicinal chemistry of selective σ 1 R and σ 2 R ligands with antiproliferative and cytotoxic activities has been provided, including major pharmacophore models and comprehensive structure–activity relationships for each main class of σR ligands.

(±)-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.

In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50 values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound’s 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.