Replacement of the Piperidine Ring with Aza-Spirocycles Reduces Cardiotoxicity of the Local Anesthetic Drug Bupivacaine

Systemic toxicity of the local anesthetic bupivacaine can lead to adverse cardiac conditions, creating a significant challenge in clinics. In this study, we examined its analogues with the central piperidine ring replaced with linear spirocyclic scaffolds. The analogues demonstrated an acceptable level of local anesthesia in mice. Notably, the spirocyclic structures exhibited significantly lower toxicity, with increases in the lethal doses of 1.3-, 2.2-, and 5.0-fold for the three tested structures, respectively. Animal studies suggested that this reduced toxicity may be attributed to lower cardiotoxicity, as evidenced by less QRS widening in isolated guinea pig hearts. Pharmacokinetic analysis in mice showed higher relative affinity of the spirocyclic analogues to plasma, while bupivacaine was more affine to the brain and heart. Our results suggest that further exploration of spirocyclic analogues of local anesthetics is warranted and support the use of spirocyclic azetidines as a replacement for the piperidine ring in drugs.