Abstract
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.
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Acknowledgements
Support was provided in part by the Dr. Jean Templeton Hugill Endowment for Anesthesia Memorial Fund; Dr. Schwarz holds the Dr. Jean Templeton Hugill Chair in Anesthesia (The University of British Columbia; Vancouver, British Columbia, Canada).
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TF, YA, RW, and SKWS have no conflict of interests to declare. EP is co-holder of a patent on the use of isovaline as an analgesic and CEO of TherExcell Pharma Inc. which is developing isovaline as a clinical analgesic. BM is a co-holder of a patent on the use of isovaline as an analgesic and a major shareholder as well as member of the board of directors for TherExcell Pharma Inc.
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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
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Fung, T., Asiri, Y.I., Wall, R. et al. Variations of isovaline structure related to activity in the formalin foot assay in mice. Amino Acids 49, 1203–1213 (2017). https://doi.org/10.1007/s00726-017-2421-6
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DOI: https://doi.org/10.1007/s00726-017-2421-6