<p>Structural Insight into the Mechanism of 4-Aminoquinolines Selectivity for the alpha2A-Adrenoceptor</p>

Abstract

Background: α 2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α 2A-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α 2A-AR subtype of traditional drugs greatly limits their clinic usage. Methods: A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α 2-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism. Results: Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α 2A-AR over α 2B-and α 2C-ARs. Besides, the affinities are of similar linker lengthdependence for each α 2-AR subtype. Among all the compounds tested, C10 has the highest affinity for α 2A-AR (pKi=−7.45±0.62), which is 12-fold and 60-fold selective over α 2B-AR and α 2C-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and "allosteric" sites of the α 2A-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99. Conclusion: The specificity of C10 for the α 2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α 2A-AR subtype selective compounds.

A Twisted Chiral Cavitand with 5-Fold Symmetry and Its Length-Selective Binding Properties

“…Similar multiple binding maxima have been observed in biological systems. , Conversely, in artificial systems, one maximum binding constant is observed upon changing the guest length in most cases. − Therefore, the host–guest system presented in this work may further our understanding of binding in biological systems.…”

Comparison of Various Intubation Deviced During Resuscitation of Covid-19-Suspected Patients by Paramedics Wearing Personal Protective Equipment

“…Such precautions are crucial as carelessness may result in self-infection or infection of future patients during subsequent medical interventions [13]. Also, in any case of contact with a patient with suspected/confirmed COVID-19, if PPE AGP was not worn bythe medical personnel, it is necessary to isolate the emergency medical team until the patient confirms or excludes COVID-19 [14]. This, in turn, results in blocking the ambulance and its entire crew and thereby reduces the responsiveness of local emergency services.…”