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

Effect of activin-A on progesterone synthesis in human luteal cells

OBJECTIVE: To examine the effect of activin-A on basal and hCG-stimulated P production by human luteal cells. DESIGN: Mixed luteal cell cultures and distinct cultures of two luteal cell types: small and large luteal cells from early and midluteal phase. SETTING: Corpora lutea (CL) were obtained from the Obstetrics and Gynecology Department of the Catholic University, Rome, Italy. PATIENTS: Fifteen nonpregnant women between 30 and 45 years of age underwent surgery for nonendocrine gynecological diseases. INTERVENTIONS: Corpora lutea were obtained at the time of hysterectomy. The luteal cells were dispersed in Ham's F-12 medium containing collagenase at 37 degrees C in shaking water bath for 2 hours, filtered, centrifuged, and resuspended in fresh medium. MAIN OUTCOME MEASURES: The cells diluted to a final concentration of 60,000 to 100,000 cells/mL of medium. After 24 hours, the cells attached to the wells and were incubated with or without hCG and/or activin-A at different concentrations. RESULTS: Activin-A starting from 25 micrograms/L significantly decreased basal and hCG (250 mIU/mL [conversion to SI unit, 1.00])-induced P production by mixed luteal cells. The small luteal cells responded to hCG (250 mIU/mL), and the treatment with activin-A (from 25 to 100 micrograms/L) reduced their basal and hCG-induced P production. Activin-A addition did not change the amount of P release by large luteal cells at any concentration. CONCLUSIONS: These results imply that activin-A plays a role in the local regulation of human CL

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

Synthesis, characterization and stereochemistry of bis(isobutyrylketonate) complexes of II group metals

Bis-(Isobutyrylketonate) complexes of II group metals have been prepared and their variable 1H-NMR spectra have been investigated. Chemical shifts values and other arguments led us to favor a pseudo-tetrahedral D2d idealized structure for all the complexes investigated but the free energy of activation for the enantiomerization (inversion at the metal tetrahedral atom) could not be determined due to the accidental isochrony of the isopropyl methyl groups in all the range of temperature investigated. © 1980

Synthesis and resolution of cis-(+/-)-methyl (1R,2S/1S2R)-2-[(4-hydroxy-4-phenylpiperidin-1-il)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [(+/-)-PPCC)]:new sigma receptor ligands with neuroprotective effect.

The enantiomers of cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [1, (+/-)-PPCC], a selective sigma ligand, were synthesized. The (+)- and (-)-enantiomers bind predominantly to sigma(1) receptors and have a reduced sigma(2) affinity. Both individually restore the astroglial oxidative status modified by glutamate, counteracting also transglutaminase-2 overexpression. They exhibited in vivo anti-opioid effects on kappa opioid (KOP) receptor-mediated analgesia. Our findings demonstrate that the enantiomers display mainly sigma(1) agonist activity and that they have neuroprotective effects