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Designing Chromane Derivatives as α 2A -Adrenoceptor Selective Agonists via Conformation Constraint.

Enhancing the selectivity of alpha2 -adrenoceptor (α2A -AR) agonists remains an unresolved issue. Herein, we reported the design of an α2A -AR agonist using the conformation constraint method, beginning with medetomidine. The structure-activity relationship indicated that the 8-substituent of chromane derivatives exerted the most pronounced effect on α2A -AR agonistic activity. Compounds A9 and B9 were identified as the most promising, exhibiting EC50 values of 0.78 and 0.23 nM, respectively. Their selectivity indexes surpassed dexmedetomidine (DMED) by 10-80 fold. In vivo studies demonstrated that both A9 and B9 dose-dependently increased the loss of righting reflex in mice, with ED50 values of 1.54 and 0.138 mg/kg, respectively. Binding mode calculations and mutation studies suggested the indispensability of the hydrogen bond between ASP1283.32 and α2A -AR agonist. In particular, A9 and B9 showed no dual reverse pharmacological effect, a characteristic exhibited by DMED in α2A -AR activation.

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