Toward the identification of the cardiac cGMP inhibited-phosphodiesterase catalytic site

Cyclic nucleotide phosphodiesterases (PDEs) comprise a complex group of enzymes; five major PDE families or classes with distinctive properties have been identified. Among these a great deal of interest has recently been focused on the so called cGMP-inhibited low K_m cAMP phosphodiesterase (cGI PDE) or PDE III. A number of positive inotropic agents, including the well-known milrinone, display a specific inhibition of PDE III as primary mechanism of action. Recent studies have been carried out to develop a pharmacophore model of the PDE III active site. We therefore performed molecular modelling and 3D-SAR studies so as to better define structural requirements for potent and selective enzymatic inhibition. The DISCO (DIStance COmparison) strategy has been applied on a set of compounds taken from literature and a milrinone analogue previously synthesized by us, all of which are characterized by a marked inotropic effect but with varying degrees of enzyme selectivity. A common pharmacophoric model was derived, validated and considered as starting point to perform a 3D-SAR study using the GRID force field and PCA (Principal Component Analysis) with the aim of rationally designing more selective inhibitors. This paper presents the results of this theoretical approach.     

Optically stimulated luminescence dating of Holocene alluvial fans,East Anatolian Fault System,Turkey

In this study, the optically stimulated luminescence dating technique was used to determine the time of deposition of alluvial sediment samples from the Türko?lu-Antakya segment of the East Anatolian Fault System (EAFS) in Turkey. The double-single aliquot regenerative dose protocol on fine grain samples was used to estimate equivalent doses (D_e). Annual dose rate was computed using elemental concentration of uranium (U) and thorium (Th) determined by using thick-source alpha counting and potassium (K) concentrations using X-ray fluorescence and/or atomic absorption spectroscopy. The environmental dose was measured in situ using α-Al₂O₃:C chips inside plastic tubes for a year. The two different bulk sediment samples collected from the Islahiye trench yielded ages of 4.54?±?0.28 and 2.91?±?0.23?ka. We also obtained a 2.60?±?0.18?ka age for the alluvial deposit in the K?ranyurdu trench and 2.31?±?0.14?ka age for an excavation area called Malzeme Oca??. These ages were consistent with the corresponding calibrated Carbon-14 (¹⁴C) ages of the region. The differences between the determined ages were insufficient to clearly distinguish the disturbance event from the effects of bioturbation, biological mixing, or other sources of D_e variation in the region. They provide a record of alluvial aggradation in the region and may determine undocumented historical earthquake events.