1-Phenyl-3-azabicyclo[3.1.0]hexane derivatives as new ligands for sigma receptors

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Investigaciones actuales en ligandos de receptores opiáceos

Relevant developments have been achieved in the last twenty years in the search for opioid agonists and antagonists with selectivity for each receptor subpopulation. Recently, new benzomorphan derivatives have been synthesized and compounds with substituted cyclopropylmethyl functionalities at N-l position showed high affinity and selectivity for K opioid receptor subpopulations. MPCB and CCB were selected as specific K agonists. The affinity ofCCB was two-fold the USO,488H one. Mixed peptide-heterocyclic compounds have been derived from these compounds and important informations on binding processes of K ligands have been obtained.En los últimos veinte años se ha llevado a cabo una intensa investigación sobre la búsqueda de agonistas y antagonistas selectivos de cada subtipo de receptores opiáceos. Recientemente, se han sintetizado nuevos derivados benzomorfánicos y compuestos con restos ciclopropilmetílicos sobre N-l que muestran alta afinidad y selectividad por los receptores K . Los compuestos MPCB y CCB se han seleccionado como agonistas específicos K. La afinidad de CCB es dos veces mayor que la del compuesto USO,488H. De estos compuestos se han derivado interesantes compuestos con estructura de peptidoheterocido y se han obtenido importantes informaciones sobre los procesos de binding a los receptores K

BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting

: The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to target. Indeed, we have recently identified a potent S2R modulator (BS148) that is effective in melanoma. To elucidate its mechanism of action, we designed and synthesized a BS148 fluorescent probe that enters SK-MEL-2 melanoma cells as assessed using confocal microscopy analysis. We show that S2R knockdown significantly reduces the anti-proliferative effect induced by BS148 administration, indicating the engagement of S2R in BS148-mediated cytotoxicity. Interestingly, BS148 treatment showed similar molecular effects to S2R RNA interference-mediated knockdown. We demonstrate that BS148 administration activates the endoplasmic reticulum stress response through the upregulation of protein kinase R-like ER kinase (PERK), activating transcription factor 4 (ATF4) genes, and C/EBP homologous protein (CHOP). Furthermore, we show that BS148 treatment downregulates genes related to the cholesterol pathway and activates the MAPK signaling pathway. Finally, we translate our results into patient-derived xenograft (PDX) cells, proving that BS148 treatment reduces melanoma cell viability and migration. These results demonstrate that BS148 is able to inhibit metastatic melanoma cell proliferation and migration through its interaction with the S2R and confirm its role as a promising target to treat cancer

In vitro human growth hormone increases human chorionic gonadotropin and progesterone secretion by human placenta at term: evidence of a modulatory role by opioids

We examined the in vitro effect of human growth hormone (hGH) on hormone placental production and the modulation by opioids of this function. Small placental fragments from 12 term placentas were incubated at 37 degrees C in a 95% air and 5% CO2 atmosphere for 4 h with various concentrations of hGH (1-1000 ng/ml) or naloxone (3-500 ng/ml). Both hGH and naloxone increased the concentrations of human chorionic gonadotropin (hCG) and progesterone in the media. The effect of the hGH was dose-dependent and statistically significant at 10 ng/ml, while naloxone was able to increase hCG and progesterone production only at the highest doses (250-500 ng/ml). The concomitant treatment with ineffective doses of naloxone and hGH was able to enhance hCG and progesterone secretion reaching levels similar to those obtained with the highest doses of hGH alone. High naloxone concentrations significantly decreased both hCG and progesterone secretion induced by high doses of hGH. This study confirms the relevance of growth hormone in sustaining placental endocrine activities and indicates an effect of opioids in modulating these function

Conformation of thianthren and 2,7-dichlorothianthren partially oriented in a nematic phase

The 1H n.m.r. spectra of thianthren and 2,7-dichlorothianthren dissolved in the Merck Nematic Phase IV were analysed and the structural parameters obtained. These molecules in solution adopt a folded conformation about the axis connecting the two sulphur heteroatoms. The angle of folding is 140.6\ub0 for thianthren and 139.8\ub0 for 2,7-dichlorothianthren. The correspondent standard deviations are \ub10.4 and \ub10.7\ub0, respectively

Intervento di ripristino della copertura arborea su un'area del parco dell'Etna interessata da colata lavica recente.

The planning and results of a reafforestation carried out on a private area occurring in the Etna Wildlife Reserve C zone are presented. The area consists of a terraced slope 70.000 square meters wide, made out of a lava flow part which dates back to 1983. At first were planted and seeded Astragalus siculus Biv. and Festuca circummediterranea Patzke, in order to set a pioneer vegetation cover; then were planted some aboreal species having a leading role in the physiognomical characterisation of the Etna landscape, like Betula aetnenis Raf., Pinus laricio Poiret, Populus tremula L. The success of the intervention is shown by the fairly quick penetration of 26 species coming from the neighbouring natural vegetation. 11 of them are pre-forestal and wood-edge entities

La vegetazione del litorale di Manfria, presso Gela (Sicilia), area soggetta a vincolo archeologico.

The results of a phytosociological investigation about a coastal area of S. Sicily, close to Gela, are presented. The coexistence of several lithological substrata, as well as the particular climatic conditions of this area, gives rise to a noteworthy floristic and vegetational biodiversity. As matter of fact, a set of N. African species are here localized, taking part to peculiar vegetation types, sometimes exclusive of this sicilian coast-stretch. The observed plant communities are represented by psammophilous associations of Cakiletea maritimae, Ammophiletea and Malcolmietalia, salt-marsh vegetation of Sarcocornietea and Phragmito-Magnocericetea, halophilous rupicolous shrublands of Crithmo-Limonietea and Pegano-Salsoletea, maquis of Oleo-Ceratonion, garigues of Cisto-Micromerietea, grasslands of the Moricandio-Lygeion sparti, subhalophilous ephemeral meadows of Stipo-Bupleuretalia semicompositi and sciaphilous nitrophylous ones of Geranio-Cardaminetalia hirsutae. Therefore, owing to the exceptional floristic and vegetational interest, this area should be protected as a wildlife reserve, and not only by an archaeological bind, as it happens at present