Highly selective CB(1) cannabinoid receptor ligands and novel CB(1)/VR(1) vanilloid receptor "hybrid" ligands

Anandamide and the metabolically stabler analogs, (R)-1'-methyl-2'-hydroxy-ethyl-arachidonamide (Met-AEA) and N-(3-methoxy-4-hydroxy-benzyl)-arachidonamide (arvanil), are CB(1) cannabinoid and VR(1) vanilloid receptors agonists. We synthesized 1',1'-dimethylheptyl-arvanil (O-1839) and six other AEA analogs obtained by addition of either a hydroxy, cyano, or bromo group on the C-20 atom of 1,1'-dimethylpentyl-Met-AEA (O-1811, O-1812 and O-1860, respectively) or 1,1'-dimethylpentyl-arvanil (O-1856, O-1895 and O-1861, respectively). The compounds were tested for their (i) affinity for CB(1) and CB(2) receptors, (ii) capability to activate VR1 receptors, (iii) inhibitory effect on the anandamide hydrolysis and on the anandamide membrane transporter, and (iv) cannabimimetic activity in the mouse 'tetrad' of in vivo assays. O-1812 is the first ligand ever proven to be highly (500- to 1000-fold) selective for CB(1) vs both VR(1) and CB(2) receptors, while O-1861 is the first true "hybrid" agonist of CB(1)/VR(1) receptors and a compound with potential therapeutic importance. The activities of the seven compounds in vivo did not correlate with their activities at either CB(1) or VR(1) receptors, thus suggesting the existence of other brain sites of action mediating some of their neurobehavioral actions in mice.     

Crinum alkaloids: their chemistry and biology

The current staus of research of free and glycosylated alkaloids occuring in members of the genus Crinum is reviewed. The distribution, isolation, spectral properties, structural properties, inter conventions and biological acitivities of these alkaloids are presented.     

Production of triploid plants from endosperm cultures of Phlox drummondii

Triploid plants of ornamental Phlox drummondii Hook. were raised from cultures of endosperm excised from immature fruits having zygotic embryo at early dicotyledonous stage. Endosperm tissue was firstly cultured with the embryo on the Murashige and Skoog’s (MS) medium supplemented with 5 μM 6-benzylaminopurine (BAP) + 10 μM α-napthaleneacetic acid (NAA) for 7 d and recultured after the embryo was removed. A friable callus appeared two weeks after removal of the embryo and it became compact callus mass in another three weeks. Upon transfer of this 5-week-old callus to the MS medium with 10 μM BAP + 2.5 μM indole-3-acetic acid (IAA), maximum percentage of green nodular shoot buds appeared from which regenerated dwarf shoots. Elongation of the dwarf shoots, however, required transfer of the individual dwarf shoots excised from the callus on the fresh medium and best results achieved on medium with low concentration of IAA (0.5 μM) in presence of 10 μM BAP. The shoots were then rooted in vitro and plants subsequently established in pots containing soil. Over 70 % of plants were triploid with a chromosome number of 2n=3x=21. Size of stem, leaves, flowers, pollen, and stomata of these triploid plants were higher and the plants were more vigorous as compared to naturally occurring diploid plants. In particular, flowers showed bright colour with enlarged central eye adding to their ornamental value.     

Synthesis of intracellular and extracellular gold nanoparticles with a green machine and its antifungal activity

Green synthesis method is being increasingly used in the development of safe, stable, and eco-friendly nanostructures with biological resources. In this study, extracellular and intracellular synthesis of gold nanoparticles (AuNPs) was carried out using green algae Chlorella sorokiniana Shihira & R.W. Fresh algae were isolated and identified from Musaözü Pond located in the province of Eskişehir and then extraction process were performed. Optimization studies were studied using pH value, metal salt concentration, and time parameters for extracellular synthesis and using only time parameter for intrasellular synthesis. Since more controlled and optimum conditions can be achieved in the production of AuNPs by extracellular synthesis, these nanoparticles (NPs) were used for characterization and antifungal activity studies. Optical, physical, and chemical properties of synthesized NPs were characterized by UV visible spectrophotometer (UV-Vis), dynamic light scattering (DLS), Zetasizer, X-Ray diffraction (XRD), Fourier transform ınfrared spectroscopy (FTIR), field emission scanning electron microscope (FE-SEM), ınductively coupled plasma mass spectrometer (ICP-MS) and transmission electron microscope (TEM) analysis. The optimum conditions for AuNPs synthesis were determined as 1 mM for HauCl₄ concentration, 6 for pH value, and 60th min for time. AuNPs obtained from extracellular synthesis from C. sorokiniana extract are 5–15 nm in size and spherical shape. TEM images of extracellular synthesis show noticeable cell wall and membrane damages, cytoplasma dissolutions, and irregularities. AuNPs obtained by intracellular synthesis are in 20–40 nm size and localized in the cell wall and cytoplasm. These NPs exhibited significant antifungal activity against C. tropicalis, C. glabrata, and C. albicans isolates. AuNPs obtained by algae-mediated green synthesis have a significant potential for medical and industrial use, and this eco-friendly synthesis method can be easily scaled for future studies.     

Appraisal of Transdermal Water-in-Oil Nanoemulgel of Selegiline HCl for the Effective Management of Parkinson’s Disease: Pharmacodynamic,Pharmacokinetic, and Biochemical Investigations

In the present study, the potential of transdermal nanoemulsion gel of selegiline hydrochloride for the treatment of Parkinson’s disease was investigated. Water-in-oil nanoemulsions were developed by comparing low- and high-energy methods and were subjected to thermodynamic stability tests, in vitro permeation, and characterization studies. In vitro studies indicated that components of nanoemulsion acted as permeation enhancers with highest flux of 3.531 ± 1.94 μg/cm²/h from nanoemulsion SB6 containing 0.5 mg selegiline hydrochloride, 3% distilled water, 21% S _mix (Span 85, Tween 80, PEG 400), and 76% isopropyl myristate by weight. SB6 with the least droplet size of 183.4 ± 0.35 nm, polydispersity index of 0.42 ± 0.06 with pH of 5.9 ± 0.32 and viscosity of 22.42 ± 0.14 cps was converted to nanoemulsion gel NEGS4 (viscosity = 22,200 ± 400 cps) by addition of Viscup160® for ease of application and evaluated for permeation, safety, and pharmacokinetic profile in Wistar rats. It provided enhancement ratio 3.69 times greater than conventional gel. NEGS4 showed 6.56 and 5.53 times increase in bioavailability in comparison to tablet and conventional gel, respectively, along with sustained effect. Therefore, the developed water-in-oil nanoemulsion gel promises to be an effective vehicle for transdermal delivery of selegiline hydrochloride.     

Discovery and characterization of endogenous cannabinoids.

The characterization of cannabinoid receptors and signal transduction mechanisms provided the impetus for the searching for endogenous ligands for this system. The result was a family of fatty acid derivatives that interact with cannabinoid receptors to varying degrees. The two ligands that have received the most attention are anandamide (AN) and 2-arachidonolyl-glycerol (Ara-Gl). They are both present in central as well as peripheral tissues. Mechanisms for the synthesis and metabolism of AN have been described. Presently, the physiological stimuli for production and release of AN are unknown. As a result, elucidation of its physiological role remains elusive. However, it seems reasonable to conclude that both AN and 2-Ara-Gl interact with cannabinoid receptors in both peripheral and central tissue to produce a wide range of effects. Administration of these ligands to laboratory animals produce effects that are quite similar to those elicited by delta9-tetrahydrocannabinol (THC), the psychoactive constituent in marijuana. Nevertheless, there are some pharmacological differences between the plant-derived THC and the endogenous cannabinoids that could be due to either pharmadynamic or pharmacokinetics dissimilarities. Extensive structure-activity relationship studies have provided some vital insights into the actions of the endogenous ligands. First and foremost, systematic structural alterations in AN have additional support that it is acting at the cannabinoid receptors in a fashion similar to that of THC. Development of metabolically stable analogs of AN, as well as those with greater receptor affinity, have helped substantiate AN and THC similarities. Nevertheless, pharmacological differences remain between the endogenous and exogenous ligands. Whether these differences are due to the nature of their interaction with the cannabinoid receptors, activation of unique signaling pathways, interactions with non-cannabinoid receptors, or pharmacokinetic considerations remain to be resolved.     

Virgin females compete for mates in the male lekking species Ceratitis capitata

Abstract. Aggressive behaviour occurring in intrasexual competition is an important trait for animal fitness. Although female intrasexual aggression is reported in several insect species, little is known about female competition and aggressive interactions in polygynous male lekking species. The interactions of female Mediterranean fruit flies, Ceratitis capitata (a male lekking species), with other females and mating pairs under laboratory conditions are investigated. Mature, unmated (virgin) females are aggressive against each other and against mating pairs, whereas immature females are not. Female aggression against other females decreases dramatically after mating; however, mated females maintain aggression against mating pairs. In addition, higher intrasexual aggression rates are observed for mature, virgin females than for virgin males of the same age. The results show that female aggressiveness is virginity related, suggesting female competition for mates. These findings have important implications for understanding the physiological aspects of a complex social behaviour such as aggression and should stimulate further research on female agonistic behaviour in male lekking mating systems.     

Steroids,chromone and coumarins from angelica officinalis

From the ethyl acetate extract of the fresh roots of Angelica officinalis var. himaliaca, besides sitosterol, pregnenolone, peucenin-7-methyl ether, osthol and 18 furanocoumarins have been characterized by spectroscopic methods, including ¹³C NMR, and some chemical transformations.