Munchserup8716

For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT1 and MT2 ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT1 and MT2, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties. From an aqueous decoction of the traditional Chinese medicine "ban lan gen" (the Isatis indigotica root), an antiviral natural product CI - 39 was isolated as an NNRTI (non-nucleoside reverse transcriptase inhibitor) (EC50 = 3.40 μM). Its novel structure was determined as methyl (1-methoxy-1H-indol-3-yl)acetamidobenzoate by spectroscopic data and confirmed by single crystal X-ray diffraction. Through synthesis and structure-activity relationship (SAR) investigation of CI - 39 and 57 new derivatives (24 with EC50 values of 0.06-8.55 μM), two optimized derivatives 10f and 10i (EC50 0.06 μM and 0.06 μM) having activity comparable to that of NVP (EC50 = 0.03 μM) were obtained. Further evaluation verified that 10f and 10i were RT DNA polymerase inhibitors and exhibited better activities and drug resistance folds compared to NVP against seven NNRTI-resistant strains carrying different mutations. Especially, 10i (EC50 = 0.43 μM) was more active to the L100I/K103N double-mutant strain as compared to both NVP (EC50 = 0.76 μM) and EFV (EC50 = 1.08 μM). The molecular docking demonstrated a possible binding pattern between 10i and RT and revealed activity mechanism of 10i against the NNRTI-resistant strains. INTRODUCTION Gallium-68 is an important radionuclide for positron emission tomography (PET) with steadily increasing applications of 68Ga-based radiopharmaceuticals for clinical use. Current 68Ga sources are primarily 68Ge/68Ga-generators, along with successful attempts of 68Ga production using a cyclotron. This study evaluated cyclotron 68Ga production and automated separation using expeditiously manufactured solid targets, demonstrates an order of magnitude improvement in yield compared to 68Ge/68Ga generators, and presents a convenient alternative to existing cyclotron production processes. A comparison of radiolabeling and preclinical PET imaging was performed with both cyclotron and generator produced 68Ga. METHODS 100 mg enriched 68Zn (99.3% 68Zn, 0.48% 67Zn, 0.1% 66Zn) pellets pressed on silver discs were bombarded for 20-75 min using 12.5 MeV proton beam energies and 10-30 μA currents. 68Ga was separated using an automated TRASIS AllinOne synthesizer employing AG 50W-X8 and UTEVA resins. Post-separatien generator and cyclotron produced 68Ga showed identical radiotracer tumor uptake and biodistribution profiles in PC3 tumor bearing mice. CONCLUSIONS Cyclotron 68Ga production provides highly scalable production with equivalent or superior quality 68Ga to a 68Ge/68Ga generator, while providing identical biodistribution and tumor uptake profiles. Our described targetry is simpler and more cost-effective than existing liquid and solid targetry, enabling a turnkey production system for multi-facility distribution of cyclotron produced 68Ga. The manufacturing simplicity described has potential applications for producing other radiometals such as 44Sc. see more ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE Our cost-effective method of solid target 68Ga production can enhance 68Ga production capabilities to meet the high demand for 68Ga-radiopharmaceuticals for research and clinical use. In two eye-tracking experiments using the Visual World Paradigm, we examined how listeners recognize words when faced with speech at lower intensities (40, 50, and 65 dBA). After hearing the target word, participants (n = 32) clicked the corresponding picture from a display of four images - a target (e.g., money), a cohort competitor (e.g., mother), a rhyme competitor (e.g., honey) and an unrelated item (e.g., whistle) - while their eye-movements were tracked. For slightly soft speech (50 dBA), listeners demonstrated an increase in cohort activation, whereas for rhyme competitors, activation started later and was sustained longer in processing. For very soft speech (40 dBA), listeners waited until later in processing to activate potential words, as illustrated by a decrease in activation for cohorts, and an increase in activation for rhymes. Further, the extent to which words were considered depended on word length (mono- vs. bi-syllabic words), and speech-extrinsic factors such as the surrounding listening environment. These results advance current theories of spoken word recognition by considering a range of speech levels more typical of everyday listening environments. From an applied perspective, these results motivate models of how individuals who are hard of hearing approach the task of recognizing spoken words. V.Such is the consistency by which performance on measures of short-term memory (STM) increase with age that developmental increases in STM capacity are largely accepted as fact. However, our analysis of a robust but almost ignored finding - that span for digit sequences (the traditional measure of STM) increases at a far greater rate than span for other verbal material - fundamentally undermines the assumption that increased performance in STM tasks is underpinned by developmental increases in capacity. We show that this digit superiority with age effect is explained by the relatively greater linguistic exposure to random sequences of digits versus other stimuli such as words. A simple associative learning process that learns incrementally from exposure to language accounts for the effect, without any need to invoke an STM mechanism, much less one that increases in capacity with age. By extension, using corpus data directed at 2-3 year old children, 4-6 year old children, and adults, we show that age-related performance increases with other types of verbal material are equally driven by the same basic associative learning process operating on the expanding exposure to language experienced by the child.