Design, Synthesis, and Bioevaluation of Dexmedetomidine Prodrug

Dexmedetomidine is commonly used in clinical practice as an anesthetic adjuvant and sedative. Unfortunately, major side effects include significant blood pressure fluctuation and bradycardia. Herein, we report the design and synthesis of four series of dexmedetomidine prodrugs aimed to alleviate hemodynamic fluctuations and simplify the administration procedure. From the in vivo experiments, all the prodrugs took effect within 5 min and did not cause significant recovery delay. The increase in blood pressure generated by one bolus of most of the prodrugs (14.57%–26.80%) was similar to that resulting from a 10 min infusion of dexmedetomidine (15.54%), which is significantly lower than the effect from a single dose of dexmedetomidine (43.55%). The decrease in heart rate induced by some prodrugs (−22.88% to −31.10%) was significantly alleviated compared with dexmedetomidine infusion (−41.07%). Overall, our work demonstrates that the prodrug strategy is useful to simplify administration procedures and mitigate hemodynamic fluctuations induced by dexmedetomidine.