Sleep deprivation increases oleoylethanolamide in human cerebrospinal fluid

This study investigated the role of two fatty acid ethanolamides, the endogenous cannabinoid anandamide and its structural analog oleoylethanolamide in sleep deprivation of human volunteers. Serum and cerebrospinal fluid (CSF) samples were obtained from 20 healthy volunteers before and after a night of sleep deprivation with an interval of about 12 months. We found increased levels of oleoylethanolamide in CSF (P = 0.011) but not in serum (P = 0.068) after 24 h of sleep deprivation. Oleoylethanolamide is an endogenous lipid messenger that is released after neural injury and activates peroxisome proliferator-activated receptor-α (PPAR-α) with nanomolar potency. Exogenous PPAR-α agonists, such as hypolipidemic fibrates and oleoylethanolamide, exert both neuroprotective and neurotrophic effects. Thus, our results suggest that oleoylethanolamide release may represent an endogenous neuroprotective signal during sleep deprivation

Three new dihydro-β-agarofuran sesquiterpenes from the seeds of Maytenus boaria

As part of a project studying the secondary metabolites extracted from the Chilean flora, we report herein three new β-agarofuran sesquiterpenes, namely (1S,4S,5S,6R,7R,8R,9R,10S)-6-acetoxy-4,9-dihydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepine-5,10-diyl bis(furan-3-carboxylate), C27H32O11, (II), (1S,4S,5S,6R,7R,9S,10S)-6-acetoxy-9-hydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepine-5,10-diyl bis(furan-3-carboxylate), C27H32O10, (III), and (1S,4S,5S,6R,7R,9S,10S)-6-acetoxy-10-(benzoyloxy)-9-hydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepin-5-yl furan-3-carboxylate, C29H34O9, (IV), obtained from the seeds of Maytenus boaria and closely associated with a recently published relative [Paz et al. (2017). Acta Cryst. C73, 451–457]. In the (isomorphic) structures of (II) and (III), the central decalin system is esterified with an acetate group at site 1 and furoate groups at sites 6 and 9, and differ at site 8, with an OH group in (II) and no substituent in (III). This position is also unsubstituted in (IV), with site 6 being occupied by a benzoate group. The chirality of the skeletons is described as 1S,4S,5S,6R,7R,8R,9R,10S in (II) and 1S,4S,5S,6R,7R,9S,10S in (III) and (IV), matching the chirality suggested by NMR studies. This difference in the chirality sequence among the title structures (in spite of the fact that the three skeletons are absolutely isostructural) is due to the differences in the environment of site 8, i.e. OH in (II) and H in (III) and (IV). This diversity in substitution, in turn, is responsible for the differences in the hydrogen-bonding schemes, which is discussed.Fil: Paz, Cristian. Universidad de la Frontera. Facultad de Ingeniería y Ciencias; ChileFil: Heydenreich, Matthias. Universitat Potsdam; AlemaniaFil: Schmidt, Bernd. Universitat Potsdam; AlemaniaFil: Vadra, Nahir. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; ArgentinaFil: Baggio, Ricardo Fortunato. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes. Gerencia de Investigación y Aplicaciones; Argentin

Drimane sesquiterpenoids purified from Drimys winteri inhibit the human α4β2 nicotinic acetylcholine receptor by noncompetitive mechanisms

ABSTRACT Background and Purpose The aim of this study is to evaluate the pharmacological activity of four natural drimane sesquiterpenoids on human (h) α4β2 nicotinic acetylcholine receptors (AChRs), the most abundant receptor subtype in the brain. Experimental Approach The drimane sesquiterpenoids, drimenin, cinnamolide, dendocarbin A, and polygodial, were purified from the Canelo tree (Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds was subsequently determined in vitro on hα4β2 AChRs by Ca2+ influx. To determine the structural components underlying the differences in inhibitory potency, structure-activity relationship, molecular docking and molecular dynamics experiments were performed on the hα4β2 AChR model. Key Results Drimane sesquiterpenoids, except dendocarbin A, inhibit hα4β2 AChRs with the following potency rank order: drimenin ~ cinnamolide > polygodial. The Ca2+ influx and structural results supported the view that these compounds inhibit hα4β2 AChRs in a noncompetitive manner, by interacting mainly with a non-luminal site located at the transmembrane region of the β2 subunit. Conclusion and Implications Drimenin sesquiterpenoids are novel hα4β2 AChR inhibitors. Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR. Drimenin derivatives might be developed as novel therapeutic approaches for the treatment of drug addictions, depression, and anxiety

Glycopolymer vesicles with an asymmetric membrane

Direct dissolution of glycosylated polybutadiene–poly(ethylene oxide) block copolymers can lead to the spontaneous formation of vesicles or membranes, which on the outside are coated with glucose and on the inside with poly(ethylene oxide)

Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes

The drimane sesquiterpenoids drimenin, cinnamolide, dendocarbin A, and polygodial were purified from the Canelo tree (Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds were determined on hα4β2, hα3β4, and hα7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: hα4β2 > hα3β4 > hα7. In the case of hα4β2 AChRs, the following potency rank order was determined (IC50's in μM): drimenin (0.97 ± 0.35) > cinnamolide (1.57 ± 0.36) > polygodial (62.5 ± 19.9) dendocarbin A (no activity). To determine putative structural features underlying the differences in inhibitory potency at hα4β2 AChRs, additional structure-activity relationship and molecular docking experiments were performed. The Ca2+ influx and structural results supported a noncompetitive mechanism of inhibition, where drimenin interacted with luminal and nonluminal (TMD-β2 intrasubunit) sites. The structure-activity relationship results, i.e., the lower the ligand polarity, the higher the inhibitory potency, supported the nonluminal interaction. Ligand binding to both sites might inhibit the hα4β2 AChR by a cooperative mechanism, as shown experimentally (nH > 1). Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR.Fil: Arias, Hugo Rubén. California Northstate University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; SuizaFil: Schmidt, Bernd. Universitat Potsdam; AlemaniaFil: Heydenreich, Matthias. Universitat Potsdam; AlemaniaFil: Paz, Cristian. Universidad de La Frontera; ChileFil: Ortells, Marcelo Oscar. Universidad de Morón; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

(-)-Pentylsedinine, a new alkaloid from the leaves of lobelia tupa with agonist activity at nicotinic acetylcholine receptor

Lobelia tupa, also called devil's tobacco, is a native plant from the center-south of Chile which has been used by the native people of Chile as a hallucinogenic and anesthetic plant. A new piperidine alkaloid, called pentylsedinine, which comprises five carbons in the side chain, was isolated from the aerial part of L. tupa, along with lobeline and lobelanidine. The structure was established on the basis of 1D and 2D NMR spectroscopy. While lobeline is a neutral antagonist at alpha 3 beta 2/alpha 3 beta 4 nAChR and alpha 7 nAChR, both lobelanidine and pentylsedinine act as partial agonists at nACh

Drimane Sesquiterpene Alcohols with Activity against <i>Candida</i> Yeast Obtained by Biotransformation with <i>Cladosporium antarcticum</i>

Fungal biotransformation is an attractive synthetic strategy to produce highly specific compounds with chemical functionality in regions of the carbon skeleton that are not easily activated by conventional organic chemistry methods. In this work, Cladosporium antarcticum isolated from sediments of Glacier Collins in Antarctica was used to obtain novel drimane sesquiterpenoids alcohols with activity against Candida yeast from drimendiol and epidrimendiol. These compounds were produced by the high-yield reduction of polygodial and isotadeonal with NaBH4 in methanol. Cladosporium antarcticum produced two major products from drimendiol, identified as 9α-hydroxydrimendiol (1, 41.4 mg, 19.4% yield) and 3β-hydroxydrimendiol (2, 74.8 mg, 35% yield), whereas the biotransformation of epidrimendiol yielded only one product, 9β-hydroxyepidrimendiol (3, 86.6 mg, 41.6% yield). The products were purified by column chromatography and their structure elucidated by NMR and MS. The antifungal activity of compounds 1–3 was analyzed against Candida albicans, C. krusei and C. parapsilosis, showing that compound 2 has a MIC lower than 15 µg/mL against the three-pathogenic yeast. In silico studies suggest that a possible mechanism of action for the novel compounds is the inhibition of the enzyme lanosterol 14α-demethylase, affecting the ergosterol synthesis

Drimane Sesquiterpene Aldehydes Control Candida Yeast Isolated from Candidemia in Chilean Patients

Drimys winteri J.R. (Winteraceae) produce drimane sesquiterpenoids with activity against Candida yeast. In this work, drimenol, polygodial (1), isotadeonal (2), and a new drimane &alpha;,&beta;-unsaturated 1,4-dialdehyde, named winterdial (4), were purified from barks of D. winteri. The oxidation of drimenol produced the monoaldehyde drimenal (3). These four aldehyde sesquiterpenoids were evaluated against six Candida species isolated from candidemia patients in Chilean hospitals. Results showed that 1 displays fungistatic activity against all yeasts (3.75 to 15.0 &micro;g/mL), but irritant effects on eyes and skin, whereas its non-pungent epimer 2 has fungistatic and fungicide activities at 1.9 and 15.0 &micro;g/mL, respectively. On the other hand, compounds 3 and 4 were less active. Molecular dynamics simulations suggested that compounds 1&ndash;4 are capable of binding to the catalytic pocket of lanosterol 14-alpha demethylase with similar binding free energies, thus suggesting a potential mechanism of action through the inhibition of ergosterol synthesis. According to our findings, compound 2 appears as a valuable molecular scaffold to pursue the future development of more potent drugs against candidiasis with fewer side effects than polygodial. These outcomes are significant to broaden the alternatives to treat fungal infections with increasing prevalence worldwide using natural compounds as a primary source for active compounds