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Structure-Activity Relationships of Alkylpyrazine Analogs and Fear-Associated Behaviors in Mice

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Abstract

Our previous studies identified alkyl pyrazine analogs in wolf urine that act as novel kairomones and induce a series of fear-associated behaviors in mice. A mixture of these alkyl pyrazines also effectively suppressed the approach of deer to a feeding area, and animals that did approach the marked area exhibited fear-associated behaviors. To investigate structure-activity relationships of alkyl pyrazines, four fear-associated behaviors - freezing, locomotion activity, odor investigation, and avoidance - were measured in experiments on female C57BL/6 J mice. Of the 17 compounds tested, 2,3-diethylpyrazine, 3-ethyl-2,5-dimethylpyrazine, and 3-ethyl-2,5-dimethylpyrazine induced all four fear-associated behaviors. 2,3,5-Trimethylpyrazine also induced three of the fear-associated behaviors, but did not decrease locomotion. Multivalent analysis of behaviors clearly demonstrated that these four compounds formed an independent cluster and were the most active. Structure-activity relationships revealed that active alkyl pyrazines inducing all four fear-associated behaviors had methyl or ethyl group(s), but not longer carbon chains, and alkyl side chains consisting of four carbon atoms in total were present in the most potent analogs. This study is the first experimental investigation of structure-activity relationships between alkyl pyrazine analogs and fear-associated behaviors in mice.

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Acknowledgements

This work was supported by the Japanese Society for the Promotion of Science KAKENHI Grant (26450141 and 15 K18573).

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Authors and Affiliations

  1. Division of Physiology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu, Ishikari, Hokkaido, 061-0293, Japan

    Kazumi Osada

  2. Department of Sensory Physiology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan

    Sadaharu Miyazono & Makoto Kashiwayanagi

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  1. Kazumi Osada
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  2. Sadaharu Miyazono
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  3. Makoto Kashiwayanagi
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Correspondence to Kazumi Osada.

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Osada, K., Miyazono, S. & Kashiwayanagi, M. Structure-Activity Relationships of Alkylpyrazine Analogs and Fear-Associated Behaviors in Mice. J Chem Ecol 43, 263–272 (2017). https://doi.org/10.1007/s10886-017-0822-3

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  • DOI: https://doi.org/10.1007/s10886-017-0822-3

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