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

Exploiting the 1-(4-fluorobenzyl)piperazine fragment for the development of novel tyrosinase inhibitors as anti-melanogenic agents: Design, synthesis, structural insights and biological profile

The development of Tyrosinase inhibitors (TYRIs) could represent an efficacious strategy for pharmacological intervention on skin pathologies related to aberrant production of melanin. Based on in silico studies we designed and tested a library of twenty-four compounds bearing the 4-(4-fluorobenzyl)piperazin-1-yl]-fragment. As result, we identified several compounds with excellent inhibit effects at low micromolar concentration against TYR from Agaricus bisporus (TyM). Among them, compound 25 (IC50 = 0.96 μM) proved to be ∼20-fold more potent than the reference compound kojic acid (IC50 = 17.76 μM) having wide applications in the cosmetics and pharmaceutical industries. The mode of interaction of active inhibitor 25 was deciphered by means of crystallography as well as molecular docking and these results were consistent with kinetic experiments. Moreover, the identified compound 25 exhibited no considerable cytotoxicity and showed anti-melanogenic effects on B16F10 melanoma cells. Therefore, a combination of computational and biochemical approaches could represent a rational guidelines for further structural modification of this class of compounds as future anti-melanogenic agents

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

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

Il progetto ECONET-COHAST: Strategie per la conservazione degli habitat costieri di Torre Manfria (Sicilia merid.)

The coexistence of several lithological substrata, together with particular geomorphologic and climatic features, are determining the exceptional floristic and faunistic interest of the coastal trait between Gela and Torre Manfria. In order to preserve and enhance coastal habitats, such area has been chosen as case-study in the Interreg project ECONET-COHAST, which involves six partners from four EU countries (Cyprus, Greece, Italy and Malta). In this paper, the main features of the area are described and the approach followed in order to implement conservation strategies accounting for the local development exigencies is illustrated. © Società Italiana di Scienza della Vegetazione