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Multidrug-resistant bacteria pose a major threat to global health, even as newly introduced antibiotics continue to lose their therapeutic value. Against this background, deeper insights into bacterial interaction with antibiotic drugs are urgently required, whereas fluorescently labeled drug conjugates can serve as highly valuable tools. Herein, the preparation and biological evaluation of 13 new fluorescent antibiotic-Cy5 dye conjugates is described, in which the tuning of the polarity of the Cy5 dye proved to be a key element to achieve highly favorable properties for various fields of application., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The high affinity dopamine D 4 receptor ligand APH199 and derivatives thereof exhibit bias toward the G i signaling pathway over β-arrestin recruitment compared to quinpirole. Based on APH199, two novel groups of D 4 subtype selective ligands were designed and evaluated, in which the original benzyl phenylsemicarbazide substructure was replaced by either a biphenylmethyl urea or a biphenyl urea moiety. Functional assays revealed a range of different bias profiles among the newly synthesized compounds, namely, with regard to efficacy, potency, and GRK2 dependency, in which bias factors range from 1 to over 300 and activation from 15% to over 98% compared to quinpirole. These observations demonstrate that within bias, an even more precise tuning toward a particular profile is possible, which─in a general sense─could become an important aspect in future drug development. Docking studies enabled further insight into the role of the ECL2 and the EPB in the emergence of bias, thereby taking advantage of the diversity of functionally selective D 4 agonists now available.

Rationale: The dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive., Objectives: The investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms., Methods: Male C57BL/6 J mice and Sprague-Dawley rats were examined in five independent experiments. We assessed APH199 (0.1-5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light-dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats., Results: APH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats., Conclusions: Our data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties., (© 2023. The Author(s).)

The electronic properties of semiconducting inorganic lead sulfide (PbS) nanocrystals (NCs) and organic linker molecules are dependent on the size of NCs as well as the used ligands. Here, we demonstrate that a weakly binding ligand can be successfully attached to PbS NCs to form a coupled organic-inorganic nanostructure (COIN) by mixing with a strong binding partner. We use the weakly binding zinc β-tetraaminophthalocyanine (Zn4APc) in combination with the strongly binding 1,2-ethanedithiol (EDT) as a mixed ligand system and compare its structural, electronic, and (photo-)electrical properties with both single-ligand COINs. It is found that binding of Zn4APc is assisted by the presence of EDT leading to improved film homogeneity, lower trap density, and enhanced photocurrent of the derived devices. Thus, the mixing of ligands is a versatile tool to achieve COINs with improved performance.

Report on a 56-year-old female exhibiting features of the multiple pterygium syndrome, e.g., puffiness and ptosis of the upper lids, hypertelorism, pterygium of the metacarpophalangeal joints, hypomobility of joints, short stature, obviously inherited as an autosomal recessive trait. In differential diagnosis distal arthrogryposis has to be considered. It is not known whether the intravitreous hemorrhage from which this patient suffered is associated with the disorder.