Cinchona Alkaloids-Derived Ammonium Salts for Long-Acting and Sensory-Selective Nerve Blockades

Local anesthetics (LAs), a type of substance with the ability of blocking nerve fiber conduction, are indispensable in clinical practice for pain relief. However, the duration of action and sensory-motor nerve selectivity of conventional LAs require further optimization. Herein, we wish to report the discovery of novel ammonium salts derived from natural cinchona alkaloids for long-acting and sensory-selective nerve blockades. The bicyclic quincoridine skeleton exhibited superior nerve blockade efficacy compared to acyclic and monocyclic analogs. Compound CLA-1-3 produced prolonged nerve blockade (over 50 h) in the rat sciatic nerve block model, possessing an IC50 value of approximately 0.39 μmol/L for voltage-gated sodium channel inhibition. On the other hand, at a concentration range of 0.30% to 0.60%, compound CLA-3-5 achieved sensory-selective nerve blockade lasting up to 3 h. The candidate molecules and underlying mechanistic insights will be valuable assets for drug development and therapeutic innovation.