Rune Sandberg

Stereoisomerism and differential activity in excitation block by local anesthetics

Abstract The enantiomers of some N -aminoalkyl derivatives of tetralin-spirosuccinimide and a -phenyl- a -propylsuccinimide which belong to a new class of local anesthetics were studied for their potency in excitation block. One enantiomer was always more active in tests in vivo and on in vitro preparations such as isolated nerves, single nerve fibers, spontaneously active crayfish ganglia and guinea-pig atria. The potency ratios ranged from about 2 to 8. The most active enantiomers bound equally to phosphatidyl-serine in vitro and inhibited calcium binding to phosphatidyl-serine and phosphatidyl-ethanolamine to the same degree. It is concluded that the enantiomers differ in their intrinsic activity on the excitable membranes and that the differences are closely related to the configuration. It is evident that although the steric interaction of the drug with the site of action is of some significance in the excitation block, the stereospecificity is fairly low. The differences in activity may be due to asymmetric molecular displacement in the membrane. However, a mechanism involving direct interaction with specific structures is not excluded, provided that they contain optically active components.