6-Amino-3-Methyl-4-(2-nitrophenyl)-1,4-Dihydropyrano[2,3-c]Pyrazole-5-Carbonitrile Shows Antihypertensive and Vasorelaxant Action via Calcium Channel Blockade.

Several 4H-pyran derivatives were designed and synthesized previously as vasorelaxant agents for potential antihypertensive drugs. In this context, the objective of the present investigation was to determine the functional mechanism of vasorelaxant action of 6-amino-3-methyl-4-(2-nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1: ) and its in vivo antihypertensive effect. Thus, compound 1: showed significant vasorelaxant action on isolated aorta rat rings pre-contracted with serotonin or noradrenaline, and the effect was not endothelium-dependent. Compound 1: induced a significant relaxant effect when aortic rings were contracted with KCl (80 mM), indicating that the main mechanism of action is related to L-type calcium channel blockade. Last was corroborated since compound 1: induced a significant concentration-dependent lowering of contraction provoked by cumulative CaCl2 adding. Moreover, compound 1: was capable to block the contraction induced by FPL 64176, a specific L-type calcium channel agonist, in a concentration-dependent manner. On the other hand, docking studies revealed that compound 1: interacts on two possible sites of the L-type calcium channel and it had better affinity energy (-7.80+/-0.00 kcal/mol on the best poses) than nifedipine (-6.86+/-0.14 kcal/mol). Finally, compound 1: (50 mg/kg) showed significant antihypertensive activity, lowering the systolic and diastolic blood pressure on spontaneously hypertensive rats (SHR) without modifying heart rate.

Exploring novel capping framework: high substituent pyridine-hydroxamic acid derivatives as potential antiproliferative agents.

PURPOSE: Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of gene expression due to their overexpression in several cancer forms. Therefore, these enzymes are considered as a potential anticancer drug target. Different synthetic and natural structures have been studied as HDACs inhibitors; based on available structural design information, the capping group is important for the biological activity due to the different interactions in the active site entrance. The present study aimed to analyze high substituted pyridine as a capping group, which included carrying out the synthesis, antiproliferative activity analysis, and docking studies of these novel compounds. METHODS: To achieve the synthesis of these derivatives, four reaction steps were performed, generating desired products 15a-k. Their effects on cell proliferation and gene expression of p21, cyclin D1, and p53 were determined using the sulphorhodamine B (SRB) method and quantitative real-time polymerase chain reaction. The HDAC1, HDAC6, and HDAC8 isoforms were used for performing docking experiments with our 15a-k products. RESULT: The products 15a-k were obtained in overall yields of 40-71%. Compounds 15j and 15k showed the highest antiproliferative activity in the breast (BT-474 and MDA-MB-231) and prostate (PC3) cancer cell lines at a concentration of 10 µM. These compounds increased p21 mRNA levels and decreased cyclin D1 and p53 gene expression. The docking study showed an increment in the strength, and in the number of interactions performed by the capping moiety of the tested molecules compared with SAHA; interactions displayed are mainly van der Waals, π-stacking, and hydrogen bond. CONCLUSION: The synthesized compounds 2-thiophene (15j) and 2-furan (15k) pyridine displayed cell growth inhibition, regulation of genes related to cell cycle progression in highly metastatic cancer cell lines. The molecular coupling analysis performed with HDAC1, HDAC6 and HDAC8 showed an increment in the number of interactions performed by the capping moiety and consequently in the strength of the capping group interaction.

Brain structures involved in the sexual behaviour of Ile de France rams with different sexual preferences and levels of sexual activity.

Using Fos, as a marker, we analysed the brain structures of rams, with different libidos or sexual preferences that had been activated by contact with males or females. Ile de France rams aged from 1.5 to 7 years were used. Fos immunoreactivity (Fos IR) was analysed in rams with high (HL) or low libido (LL) after 90 min of direct contact with females (HL DirF n=7 or LL DirF n=7) or in rams of high libido having indirect contact through a fence, with females (HL IndF n=6) or males (HL IndM n=5) and finally, in males who preferred other males as partners by indirect contact through a fence with males (MO IndM n=4). Direct or indirect contact with a preferred sexual partner (LL DirF, HL Dir F, HL IndF, MO IndM) induced the appearance of Fos-IR cells in several diencephalic and cortical structures. Conversely, indirect contact with males did not induce Fos-IR in males interested in females (HL IndM). In the medial preoptic area (MPOA), the paraventricular nucleus and the medial bed nucleus of the stria terminalis the cell density of Fos IR cells was higher in HL Dir F than in LL DirF suggesting involvement in sexual motivation whereas only the MPOA seemed involved the consummatory component of sexual behaviour (Fos IR density HL DirF>HL IndF). The enthorinal cortex was the only structure specifically activated by males attracted to other males (Fos IR density MO IndM>HL IndM) whereas Fos IR density did not differ between the HL IndF and HL IndM groups.

Optical slicing of human retinal tissue in vivo with the adaptive optics scanning laser ophthalmoscope.

We present imaging results in human retinal tissue in vivo that allowed us to determine the axial resolution of the adaptive optics scanning laser ophthalmoscope (AOSLO). The instrument is briefly described, and the imaging results from human subjects are compared with (a) the estimated axial resolution values for a diffraction-limited, double-pass instrument and (b) the measured one for a calibrated diffuse retinal model. The comparison showed that the measured axial resolution, as obtained from optical sectioning of human retinas in vivo, can be as low as 71 microm for a 50 microm confocal pinhole after focusing a 3.5 mm beam with a 100 mm focal-length lens. The axial resolution values typically fall between the predictions from numerical models for diffuse and specular reflectors. This suggests that the reflection from the retinal blood vessel combines diffuse and specular components. This conclusion is supported by the almost universal interpretation that the image of a cylindrical blood vessel exhibits a bright reflection along its apex that is considered specular. The enhanced axial resolution achieved through use of adaptive optics leads to an improvement in the volume resolution of almost 2 orders of magnitude when compared with a conventional scanning laser ophthalmoscope and almost a factor of 3 better than commercially available optical coherence tomographic instruments.

Theoretical modeling and evaluation of the axial resolution of the adaptive optics scanning laser ophthalmoscope.

We present axial resolution calculated using a mathematical model of the adaptive optics scanning laser ophthalmoscope (AOSLO). The peak intensity and the width of the axial intensity response are computed with the residual Zernike coefficients after the aberrations are corrected using adaptive optics for eight subjects and compared with the axial resolution of a diffraction-limited eye. The AOSLO currently uses a confocal pinhole that is 80 microm, or 3.48 times the width of the Airy disk radius of the collection optics, and projects to 7.41 microm on the retina. For this pinhole, the axial resolution of a diffraction-limited system is 114 microm and the computed axial resolution varies between 120 and 146 microm for the human subjects included in this study. The results of this analysis indicate that to improve axial resolution, it is best to reduce the pinhole size. The resulting reduction in detected light may demand, however, a more sophisticated adaptive optics system. The study also shows that imaging systems with large pinholes are relatively insensitive to misalignment in the lateral positioning of the confocal pinhole. However, when small pinholes are used to maximize resolution, alignment becomes critical.

Adaptive optics scanning laser ophthalmoscopy.

We present the first scanning laser ophthalmoscope that uses adaptive optics to measure and correct the high order aberrations of the human eye. Adaptive optics increases both lateral and axial resolution, permitting axial sectioning of retinal tissue in vivo. The instrument is used to visualize photoreceptors, nerve fibers and flow of white blood cells in retinal capillaries.