Designing Chromane Derivatives as α_2A-Adrenoceptor Selective Agonists via Conformation Constraint

Enhancing the selectivity of alpha₂-adrenoceptor (α_2A-AR) agonists remains an unresolved issue. Herein, we reported the design of an α_2A-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 α_2A-AR agonistic activity. Compounds <b>A9</b> and <b>B9</b> 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 <b>A9</b> and <b>B9</b> 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 ASP128^3.32 and α_2A-AR agonist. In particular, <b>A9</b> and <b>B9</b> showed no dual reverse pharmacological effect, a characteristic exhibited by DMED in α_2A-AR activation.