20224-43-5Relevant academic research and scientific papers
Barbiturates bind in the GLIC ion channel pore and cause inhibition by stabilizing a closed state
Fourati, Zaineb,Ruza, Reinis Reinholds,Laverty, Duncan,Drège, Emmanuelle,Delarue-Cochin, Sandrine,Joseph, Delphine,Koehl, Patrice,Smart, Trevor,Delarue, Marc
, p. 1550 - 1558 (2017)
Barbiturates induce anesthesia by modulating the activity of anionic and cationic pentameric ligand-gated ion channels (pLGICs). Despite more than a century of use in clinical practice, the prototypic binding site for this class of drugs within pLGICs is yet to be described. In this study, we present the first X-ray structures of barbiturates bound to GLIC, a cationic prokaryotic pLGIC with excellent structural homology to other relevant channels sensitive to general anesthetics and, as shown here, to barbiturates, at clinically relevant concentrations. Several derivatives of barbiturates containing anomalous scatterers were synthesized, and these derivatives helped us unambiguously identify a unique barbiturate binding site within the central ion channel pore in a closed conformation. In addition, docking calculations around the observed binding site for all three states of the receptor, including a model of the desensitized state, showed that barbiturates preferentially stabilize the closed state. The identification of this pore binding site sheds light on the mechanism of barbiturate inhibition of cationic pLGICs and allows the rationalization of several structural and functional features previously observed for barbiturates.
Chiral barbituric acid compound and preparation method thereof
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, (2021/02/06)
The invention discloses a chiral barbituric acid compound and a preparation method thereof. The chiral barbituric acid compound is an optically active compound having a structure represented by the following formula (1), and comprises a levorotatory body or a dextrorotatory body having the same chemical general formula: in the formula: * represents a chiral carbon atom, substituent groups R1 and R3 are respectively and independently selected from alkyl, the substituent R2 is selected from alkyl or allyl, and X is selected from O or S. Racemic propargyl carbonate and malonate compounds are usedas initial raw materials, bis-(1, 5-cyclooctadiene) nickel metal is used as a catalyst, a chiral phosphine reagent is used as a ligand, Lewis acid is used as a co-catalyst, and asymmetric propargyl reaction and subsequent reduction and condensation reaction are performed under the assistance of alkali, the chiral barbituric acid compound is prepared with high yield, high enantioselectivity and approximate gram scale in an accurate and rapid mode for the first time, and the method has biomedical practicability and industrial application prospects.
