Variations of isovaline structure related to activity in the formalin foot assay in mice

Current centrally acting analgesics such as opioids are associated with adverse effects that limit their use and threaten patient safety. Isovaline is a novel prototype analgesic that produces peripheral antinociception in several pain models with little or no effect on the central nervous system. The aim of this study was to establish a preliminary structure-activity relationship for isovaline derivatives by assaying efficacy in the formalin foot assay and central adverse effect profile in mice. Selected compounds were tested using the formalin foot assay to determine efficacy in reducing formalin-induced behaviors. Of the compounds tested, R-isovaline, S-isovaline, and 1-amino-1-cyclobutanecarboxylic acid reduced nocifensive behavior in phase II of the assay. These effects occurred without affecting performance on the rotarod, indicating that the reduction in nocifensive behaviors was not due to sedation or motor incoordination. Modifications to isovaline that increased its steric size without a cyclobutane ring formation produced compounds with no activity in the formalin foot assay. These findings indicate that the conformational stability of isovaline or the ability to form a cyclobutane ring is necessary for activity in the formalin foot assay.