The Effects of Benzene Substituents and Intermediate Linkage on Local Anesthetic Effectiveness

There are many experimental studies on the effectiveness of clinically effective local anesthetics (LA). Although an atomic analysis of LAs would contribute to understanding the factors that influence their effectiveness, there have been no theoretical studies performed thus far. Previous prominent papers in the field have examined the aromatic ring and amine terminal of LAs in great detail. In this paper, I establish which type of intermediate linkage – ester or amide – lends to a relatively greater effectiveness. I also elucidate the extent to which substitutions on the LA’s benzene ring differentially influence amino esters’ and amino amides’ relative effectiveness. Using novel structure-based drug design (SBDD) techniques, I observed that LA effectiveness is influenced more by benzene ring substitutions and, to a lesser degree, by the type of intermediate linkage.