Fentanyl(Fen)analogs,clinically used anesthetic adjuvants,are often trouble with overdose‐induced adverse effects due torapid entry into the brain plus short retention time.Advanced approaches that can relieve relate...Fentanyl(Fen)analogs,clinically used anesthetic adjuvants,are often trouble with overdose‐induced adverse effects due torapid entry into the brain plus short retention time.Advanced approaches that can relieve related life‐threatening symptomswithout compromising their anesthetic efficacy are urgently needed to satisfy these special requirements.Herein,we proposethat utilization of a well‐matched macrocycle,terphen[3]arene sulfate(TP3S)as a molecular‐level brake for Fen via thepharmacokinetic mode to execute this task.NMR and titration experiments confirm that TP3S possessed strong complexationability toward Fen with an association constant of(1.36±0.12)×10^(6)M^(−1).Then,Transwell assays demonstrate that TP3S itselfis unable to cross the blood–brain barrier,and codosed with Fen could effectively decelerate its velocity of entering the brain.Respiration‐related evaluations and pharmacodynamics analyses reveal that administration of such a brake alleviatesFen‐induced respiratory depression without losing its effectiveness.The therapeutic index of Fen/TP3S is calculated to be~57%higher than that of Fen alone,and through pharmacokinetic studies,it has been clarified that ameliorating Fen's therapeuticoutcome stemmed from reducing the initial brain concentration of Fen and maintaining its effective dose for a longer time.Thissupramolecular approach could also act on other opioids as long as strong binding was achieved.展开更多
基金supported by the National Natural Science Foundation of China(22171286 and 22201212).
文摘Fentanyl(Fen)analogs,clinically used anesthetic adjuvants,are often trouble with overdose‐induced adverse effects due torapid entry into the brain plus short retention time.Advanced approaches that can relieve related life‐threatening symptomswithout compromising their anesthetic efficacy are urgently needed to satisfy these special requirements.Herein,we proposethat utilization of a well‐matched macrocycle,terphen[3]arene sulfate(TP3S)as a molecular‐level brake for Fen via thepharmacokinetic mode to execute this task.NMR and titration experiments confirm that TP3S possessed strong complexationability toward Fen with an association constant of(1.36±0.12)×10^(6)M^(−1).Then,Transwell assays demonstrate that TP3S itselfis unable to cross the blood–brain barrier,and codosed with Fen could effectively decelerate its velocity of entering the brain.Respiration‐related evaluations and pharmacodynamics analyses reveal that administration of such a brake alleviatesFen‐induced respiratory depression without losing its effectiveness.The therapeutic index of Fen/TP3S is calculated to be~57%higher than that of Fen alone,and through pharmacokinetic studies,it has been clarified that ameliorating Fen's therapeuticoutcome stemmed from reducing the initial brain concentration of Fen and maintaining its effective dose for a longer time.Thissupramolecular approach could also act on other opioids as long as strong binding was achieved.
