[Relationships between ototoxicities and chemical structures of ototoxic drugs]

The relationships between degrees of ototoxicity and the chemical structures of ototoxic drugs were investigated using isolated bullfrog semicircular canals. Thirteen derivatives of tuberactinomycin (Tum), a peptide antibiotic with pharmacological characteristics similar to those of kanamycin, were prepared by replacing the R1 branch with various amino acids. The degrees of ototoxicity were measured in these derivatives as well as in different kinds of aminoglycoside (AGs) antibiotics (TOB, GM, NTL, ISP, AMK). In order to measure the degree of ototoxicity, the ampullary nerve action potential of isolated bullfrog posterior semicircular canal, in response to mechanical endolymphatic flow, was recorded in Frog Ringer's solution and in the presence of different amounts of the various drugs. The degree of ototoxicity was determined by the amount of decrease in the maximal spike account. The degrees of ototoxicity of AGs were calculated to be in the order TOB > GM > ISP > AMK > NTL. This result was in agreement with those of previous morphological investigations. The derivatives of Tum with an R1 branch containing an acidic or a basic amino acid showed greater ototoxicities than those containing aliphatic side chains. The degree of ototoxicity of each drug tended to differ with each concentration, in both AG and Tum derivatives. Thus, the result indicate that chemical structure may be closely related to the degree of ototoxicity.