1,721,029 research outputs found
Sigma Receptor Research: Progress Towards Diagnostic and Therapeutic Uses of Sigma Ligands
No full textSigma-2 receptor: Past, present and perspectives on multiple therapeutic exploitations
No full textIdentification of sigma-2 receptor (sig-2R) has been controversial. Nevertheless, interest in sig-2R is high for its overexpression in tumors and potentials in oncology. Additionally, sig-2R antagonists inhibit Aβ binding at neurons, blocking the cognitive impairments of Alzheimer's disease. The most representative classes of sig-2R ligands are herein treated with focus on compounds that served to study sig-2R biology and to produce sig-2R: fluorescent ligands; multifunctional anticancer agents; and targeting nanoparticles. Although fluorescent ligands serve as 'green' pharmacological tools, sig-2R-multifunctional conjugates and sig-2R-targeted nanoparticles show how sig-2R targeting increases the activity of anticancer drugs in tumors with reduced toxicity. Altogether, this review draws a picture of the multiple approaches of sig-2R ligands in cancer therapy and as Alzheimer's disease modifying disease agents
Classes of sigma2 ( o-2) receptor ligands: structure affinity relationship (SAfiR) studies and antiproliferative activity
No full textAlthough several pieces of information are still missing about sigma-2 receptor, the production of high affinity sigma-2 receptor ligands allowed important acquisitions. Morphans such as CB64D and CB184 were the first truly 2-selective ligands synthesized, and their use in cell cultures highlighted the relationship between sigma-2 receptors and cell proliferation, shedding light on important diagnostic and therapeutic potentials with which sigma-2 ligands are endowed. The most significant classes of compounds are herein discussed. The design and Structure-Affinity Relationship studies (SAfiR) of 2 receptor ligands belonging to the classes of morphans, indoles (siramesine analogues), granatanes, flexible benzamides and N-cyclohexylpiperazines are reported, together with the biological results which these compounds provided giving a crucial contribution to the sigma-2 receptor research. The pharmacophore models which were generated on the basis of different classes of the sigma-2 ligands and the attempts for 2 receptor purification are briefly described
Live imaging reveals a new role for the sigma-1 (σ1) receptor in allowing microglia to leave brain injuries
Full text linkMicroglial cells are responsible for clearing and maintaining the central nervous system (CNS) microenvironment.
Upon brain damage, they move toward injuries to clear the area by engulfing dying neurons.
However, in the context of many neurological disorders chronic microglial responses are responsible
for neurodegeneration. Therefore, it is important to understand how these cells can be “switched-off”
and regain their ramified state. Current research suggests that microglial inflammatory responses can be
inhibited by sigma () receptor activation. Here, we take advantage of the optical transparency of the
zebrafish embryo to study the role of 1 receptor in microglia in an intact living brain. By combining
chemical approaches with real time imaging we found that treatment with PB190, a 1 agonist, blocks
microglial migration toward injuries leaving cellular baseline motility and the engulfment of apoptotic
neurons unaffected. Most importantly, by taking a reverse genetic approach, we discovered that the role
of 1 in vivo is to “switch-off” microglia after they responded to an injury allowing for these cells to
leave the site of damage. This indicates that pharmacological manipulation of 1 receptor modulates
microglial responses providing new approaches to reduce the devastating impact that microglia have in
neurodegenerative diseases
Collateral Sensitivity of sigma2 Receptor ligands: Potentials in the Treatment of Multidrug Resistant Tumors
Full text linkRigid versus flexible anilines or anilides confirm the bicyclic ring as the hydrophobic portion for optimal σ2 receptor binding and provide novel tools for the development of future σ2 receptor PET radiotracer
No full textDespite their uncertain identification, s2 receptors are promising targets for the development of diagnostics
and therapeutics for tumor diseases. Among the s2 ligands developed, the class of the flexible benzamides
furnished an optimal pharmacophore for s2 receptor high affinity ligands. A recent investigation suggested
that flexible benzamides bind s2 receptors in a bicyclic-like conformation due to an intramolecular H-bond,
with 3,4-dihydroisoquinolinone derivatives reaching excellent s2 affinity and selectivity. Herein, the
bicyclic-preferred conformation for s2 binding was confirmed through the development of 3,4-
dihydroquinolin-(1H)2-one isomeric derivatives, 1,2,3,4-tetrahydroquinolines and the corresponding
flexible anilides and anilines, all linked to the 6,7-dimethoxytetrahydroisoquinoline as a basic moiety. 3,4-
Dihydroisoquinolin-(1H)2-one (10a) and 1,2,3,4-tetrahydroisoquinoline (11b) emerged for high s2 affinity
combined to an excellent s2 versus s1 selectivity. In particular, compound 11b with its low nanomolar s2
affinity and impressive 2807-fold s2 versus s1 selectivity largely exceeded the biological profile of the
best 3,4-dihydroisoquinolin-(2H)1-one reference compounds (1). Because of the absence of a cytotoxic
effect, the modest interaction with the P-gp, an appropriate lipophilicity and the presence of easily
radiolabeling functions, 11b deserves further investigation for the imaging of s2 receptors via PET in tumor
The sigma-1 receptor antagonist PB212 reduces the Ca2+-release through the inositol (1, 4, 5)-triphosphate receptor in SK-N-SH cells
No full textSigma-1 receptors are specifically located at the endoplasmic reticulum–mitochondrion interface, but upon stimulation by ligands or under prolonged cellular stress, they translocate to other areas of the cell. Sigma-1 receptors are involved in the regulation of intracellular [Ca2+] by affecting the Ca2+-influx or the release from intracellular stores. In SK-N-SH cells, we measured the affinity of 4-methyl-1-[4-(6-methoxynaphthalen-1-yl)butyl]piperidine (PB212) at sigma-1 receptor by using a competition binding assay with specific radioligand; we obtained a Ki value = 316 ± 19 nM. PB212 also showed an antiproliferative effect in SK-N-SH cells (EC50 = 32 ± 4 μM) but had no effect in MCF7 cells, which only express sigma-2 receptor; these findings suggest that PB212 behaves as a sigma-1 receptor antagonist. We have studied the effect of PB212 on Ca2+ homeostasis of the SK-N-SH cell line with the fluorescent probe Fura-2. 100 μM PB212 induced a Ca2+-efflux from the endoplasmic reticulum through the inositol (1, 4, 5)-trisphosphate (IP3) receptor. Moreover, [PB212] ranging from 1 to 100 μM reduced the Ca2+-response, triggered by carbachol or bradykinin that engage the phospholipase C/IP3 pathway; such a response is generally increased by sigma-1 receptor agonists. On the other hand, PB212 did not reduce the Ca2+-response mediated by IP3 in LoVo cells, which do not express neither sigma-1 nor sigma-2 receptors, and in MCF7 cells. The fact that the activity of the sigma-1 receptor can be experimentally modulated by agonists and antagonists supports the intriguing hypothesis that some endogenous molecules, unknown at the moment, modulate the sigma-1 receptor and its cellular targets
Zervimesine, a Small Sigma-2 Receptor Selective Modulator for Alzheimer’s Disease
No full textZervimesine is a small molecule, able to cross the blood−brain barrier,
readily available by straightforward organic chemistry processes, showing few “off-target” effects, but displays a potent and selective S2R modulator profile. Evidence suggests Zervimesine can protect synapses and neurons by preventing the toxic effects of soluble Aβ oligomers
Sintesi di [3H]-1-cicloesil-4-[3-(5-metossi-1,2,3,4-tetraidronaftalen-1-il)-n-propil]piperazina ([3H]-PB28) il primo potente e selettivo strumento farmacologico nella valutazione biologica di recettori sigma-2
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