Novel Local Anesthetics Demonstrate Isomer-Dependent Analgesia in Mice

Clinically there is a need for local anesthetics with a greater specificity of action and longer duration. We have synthesized a series of local anesthetic derivatives we call boronicaines in which the benzene ring of lidocaine is replaced with ortho-, meta-, dimethyl meta- and para-carborane clusters. A carborane cluster is an icosahedral cage comprised of ten boron and two carbon atoms (C2B10H12) which is more hydrophobic than a benzene ring. The boronicaine derivatives were tested for their analgesic activity and compared to lidocaine using standard procedures in mice following a plantar injection. The compounds differed in their analgesic activity in the following order: ortho-carborane = dimethyl meta-carborane > para-carborane > lidocaine > meta-carborane derivative. Both ortho-boronicaine and dimethyl meta-boronicaine had longer durations of analgesia than lidocaine. Differences in analgesic efficacies are rationalized by variations in chemical structure and protein binding characteristics. Preliminary studies using expressed voltage gated Na channels show that these compounds block channel currents in a state dependent and reversible manner. Financial support to G.R.K. from the University of Missouri Intellectual Property Fast Track Funding Program is acknowledged.