Banu Cahide Tel

Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance

In an effort to establish new candidates with improved analgesic and anti-inflammatory activities and lower ulcerogenic risk, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one derivatives of ibuprofen were synthesized. All compounds were evaluated for their in vivo anti-inflammatory and analgesic activities in mice. Furthermore, the ulcerogenic risks of the compounds were determined. In general, none of the compounds represent a risk for developing stomach injury as much as observed in the reference drugs ibuprofen and indomethacin. The compounds carrying a 3-phenyl-2-propenylidene (1a), (biphenyl-4-yl)methylidene (1f) and (1-methylpyrrol-2-yl)methylidene (1n) at the 6th position of the fused ring have been evaluated as potential analgesic/anti-inflammatory agents without a gastrointestinal side effect. These new compounds, therefore, deserve further attention to develop new lead drugs.

Reactive oxygen species-induced impairment of endothelium-dependent relaxation in rat aortic rings: protection by L-arginine.

The protective effect of L-arginine against reactive oxygen species-induced impairment of endothelium-dependent vasorelaxation was investigated in isolated ring preparations of rat aorta. The aortic rings were subjected to reactive oxygen species generated by the electrolysis of the bathing solution or incubation with H2O2. Endothelium-dependent relaxation in response to acetylcholine of precontracted aortic rings was attenuated when the rings were exposed to reactive oxygen species or H2O2. Incubation prior to electrolysis with either L-arginine, the endogenous precursor of nitric oxide (NO), or sodium nitroprusside, an exogenous donor of NO, protected the aortic rings against the impairment of endothelium-dependent relaxation. However, D-arginine and glycine, amino acids which do not produce NO, also afforded protection in this model. Therefore, not only the increased synthesis of NO but also the oxidation of L-arginine, with concomitant disproportionation of reactive oxygen species, may be responsible for the protective effect against reactive oxygen species-induced loss of the endothelial response to acetylcholine in isolated rat aorta.

Novel thiazolo[3,2-b]-1,2,4-triazoles derived from naproxen with analgesic/anti-inflammatory properties: Synthesis, biological evaluation and molecular modeling studies.

3-Substituted-1,2,4-triazole-5-thiones are versatile synthetic intermediates for the preparation of several biologically active N-bridged heterocyclic compounds, given that they have two reactive sites, thiocarbonyl and an amine nitrogen (N1/N4). For several years, our interest has focused on the synthesis of novel heterocyclic systems derived from 3-substituted-1,2,4-triazole-5-thiones having analgesic/anti-inflammatory activity. In this study, a series of novel thiazolo[3,2-b]-1,2,4-triazole-6(5H)-one derivatives bearing naproxen was synthesized and evaluated for their in vivo analgesic and anti-inflammatory properties in acute experimental pain and inflammation models. The compounds were also tested for their ulcerogenic potential. Our findings showed that all the newly synthesized derivatives attenuate nociception and inflammation compared with a control. All the synthesized compounds exhibited much lower ulcerogenic risk than the standard drugs indomethacin and naproxen. Some compounds with significant analgesic and/or anti-inflammatory activities as well as low ulcer scores were further evaluated for in vitro COX-1 and COX-2 inhibitory potential in a COX-catalyzed prostaglandin biosynthesis assay. Among the tested compounds, compound 1q showed the highest selectivity index (SI) of 4.87. The binding mode for some of the tested compounds to the cyclooxygenase (COX) enzymes was predicted using docking studies.

Effect of intermedin/adrenomedullin 2 on the pulmonary vascular bed in hypoxia-induced pulmonary hypertensive rats

Aims: This study aimed to investigate the effect and mechanism of action of intermedin/adrenomedullin2 (IMD/AM2) on the pulmonary vascular bed in pulmonary hypertensive rats. Materials and methods: Male Sprague‐Dawley rats were exposed to hypobaric hypoxia for 3 weeks to induce pulmonary hypertension (PHT). The development of PHT was confirmed by histopathological analyses and measurement of hematocrit, basal perfusion pressure, and right ventricle hypertrophy. Subsequently, the effect of IMD/AM2 in pulmonary hypertensive rats was assessed with both, isolated organ bath and isolated lung perfusion studies. Key findings: In the PHT group, the basal perfusion pressure and % hematocrit were increased, and right ventricle hypertrophy occurred after 3 weeks of hypoxia exposure. Increased medial wall thickness was also observed in the pulmonary artery with histopathological analysis. In the PHT, the nitric oxide‐mediated vasodilation caused by IMD/AM2 in the pulmonary vascular bed and this was as potent as the control group. Acetylcholine responses were also protected in pulmonary hypertensive rats. Significance: Our results showed for the first time in in vitro studies that IMD/AM2 administration causes potent, concentration‐dependent vasodilation in the main and resistance pulmonary arteries of rats with PHT. Based on these results, IMD/AM2 might be considered as a future therapeutic target for PHT treatment.

Design and Synthesis of 1,2,4-Triazolo[3,2-b]-1,3,5-thiadiazine Derivatives as a Novel Template for Analgesic/Anti-Inflammatory Activity

Previously, we demonstrated that certain heterocyclic compounds derived from 3‐substituted‐1,2,4‐triazole‐5‐thiones had promising analgesic/anti‐inflammatory activities together with low ulcerogenic properties. Therefore, we sought to design and synthesize new derivatives of triazol‐5‐thiones‐fused heterocycles. In the present study, a series of novel bis‐Mannich bases, namely 2,6‐disubstituted‐6,7‐dihydro‐5H‐1,2,4‐triazolo[3,2‐b]‐1,3,5‐thiadiazines (1a–d, 2a–c, and 3a–d), were synthesized and characterized to assess their possible anti‐inflammatory/analgesic properties. Additionally, their ability to induce gastric toxicity was also evaluated. Several of the condensed compounds produced a degree of analgesic activity comparable to reference drugs in both the hot plate and tail‐flick tests. A strong anti‐inflammatory effect was observed for the derivatives carrying a benzyl group at the second position (2a–c). The majority of the prepared compounds caused comparatively less gastrointestinal (GI) side effects than the reference drugs naproxen and indomethacin did. These results showed that 1,2,4‐triazolo[3,2‐b]‐1,3,5‐thiadiazine derivatives might afford a safer alternative to currently available analgesic/anti‐inflammatory agents for the treatment and management of inflammatory disease and pain.

Mechanism of adrenomedullin 2/intermedin mediated vasorelaxation in rat main pulmonary artery

HighlightsIMD/ADM2 provide vasorelaxation through CGRP receptors in rat pulmonary artery.cAMP/PKA is one of the important pathway in the response.Endothelial BKCa channels mediate the IMD/ADM2 induced NO production.The vasorelaxation completely calcium‐dependent.Endothelial L‐type voltage sensitive calcium channels have role in the mechanism of vasorelaxation. &NA; Adrenomedullin 2/intermedin (AM2/IMD) is a member of calcitonin related gene peptide family and an important nitric oxide mediated vasorelaxant in various vascular beds. However, the mechanism of post receptor‐interaction is not clear and may differ depending on tissue type and species. In this study, we aimed to investigate the exact mechanism and the role of BKCa and calcium channels on the vasorelaxant effect of AM2/IMD in rat PA. Changes in the AM2/IMD‐mediated vasorelaxation were evaluated in the presence of various inhibitors. CGRP(8‐37) (10−6 M), L‐NAME (10−4 M), ODQ (10−5 M), SQ22536 (10−4 M), H89 (10−6 M), TEA (10−2 M), iberiotoxin (3 × 10−7 M), and verapamil (10−5 M), all partly or completely inhibited the vasorelaxation. The relaxation was also abolished by removal of the endothelium, or in KCl precontracted PAs. AM2/IMD did not elicit vasorelaxation in the Ca2+‐free conditions. However, the vasorelaxation was not inhibited with AM(22‐52) (10−6 M), 4‐AP (3 × 10−3 M), glibenclamide (10−5 M), apamin (3 × 10−7 M), TRAM‐34 (10−5 M), and La+3 (10−4 M). AM2/IMD −induced changes in intracellular calcium levels and isometric force were monitored simultaneously in fura‐2‐loaded, endothelium‐intact PAs. The AM2/IMD‐induced increase in intracellular Ca2+ concentration was inhibited in the presence of iberiotoxin and verapamil, whereas no change was observed with La3+ incubation. Our data suggest that the cAMP/PKA pathway is one of the important pathways AM2/IMD‐induced vasorelaxation. AM2/IMD acts through activation of endothelial BKCa and subsequently causes hyperpolarization of the endothelial cell membrane. The hyperpolarization induces Ca2+ influx, which leads to NO production and subsequent vasorelaxation.

Effects of GPER-1 Receptor Activation on the Reactivity of Pulmonary Vascular Bed and Its Possible Protective Role on Ischemia /Reperfusion Injury

Estrogens have remarkable roles in various diseases and physiological events. The recent studies indicate that estrogens exhibit rapid effects such as calcium influx or release of nitric oxide via receptors on the cell membrane or on endoplasmic reticulum. This receptor is called GPER-1 (G protein-coupled estrogen receptor-1). In many previous studies, acute administration of GPER-1 selective agonist G1 reduced ischemia/reperfusion (I/R) injury in heart. In this study, the effect of G1 on the pulmonary vascular bed was investigated using isolated organ bath and isolated lung perfusion. The effect of pre-ischemic acute G1 treatment on lung I/R injury was assessed with post-I/R acetylcholine (ACh) or sodium nitroprusside (SNP) administration. Lungs wet/dry weight ratios were measured to determine the role of acute G1 administration on lung edema due to I/R injury. G1 was not cause a vasorelaxation in precontracted pulmonary arteries. The acute G1 pre-administration was increased the responses of ACh and SNP in I/R injury, however this increase was not statistically significant compared to control. There was no change on lung wet/dry weight ratio between the treatment and control groups. The vasorelaxation responses to ACh and SNP were not different between male and female rats. In our study, G1 caused a slight vasorelaxation in pulmonary vascular bed. There was no significant increase in the vasorelaxations with G1 treatment after I/R injury. Our results suggest that considering the presence of GPER-1 in lung tissue, GPER-1 should be evaluated in detail with further studies.