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Worldwide populations of ticks have developed resistance to acaricides, underscoring the need for novel target discovery for tick control. The arthropod\u2010specific\n                      <jats:italic>R. microplus<\/jats:italic>\n                      kinin receptor is such a target, previously validated by silencing, which resulted in female reproductive fitness costs, including a reduced percentage of eggs hatching.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      In order to identify potent small molecules that bind and activate or inhibit the kinin receptor, a high\u2010throughput screening (HTS) assay was developed using a CHO\u2010K1 cell line expressing the recombinant tick kinin receptor (BMLK\n                      <jats:sub>3<\/jats:sub>\n                      ). A total of ~20\u2009000 molecules from a random in\u2010house small molecule library were screened in a \u2018dual\u2010addition\u2019 calcium fluorescence assay. This was followed by dose\u2013response validation of the hit molecules identified both from HTS and an\n                      <jats:italic>in silico<\/jats:italic>\n                      screen of ~390\u2009000 molecules. We validated 29 antagonists, 11 of them were full antagonists with IC\n                      <jats:sub>50<\/jats:sub>\n                      values between 0.67 and 8\u2009\u03bcmol\u2009L\n                      <jats:sup>\u20131<\/jats:sup>\n                      . To explore the structure\u2013activity relationships (SAR) of the small molecules, we tested the activities of seven analogs of the most potent identified antagonist, additionally discovering three full antagonists and four partial antagonists. These three potent antagonists (IC\n                      <jats:sub>50<\/jats:sub>\n                      &lt;\u20093.2\u2009\u03bcmol\u2009L\n                      <jats:sup>\u20131<\/jats:sup>\n                      ) were validated\n                      <jats:italic>in vitro<\/jats:italic>\n                      using the recombinant mosquito kinin receptor and showed similar antagonistic activities.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , these three compounds also inhibited the mosquito hindgut contraction rate induced by a myotropic kinin agonist analog 1728.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>Antagonists identified in this study could become pesticide leads and are reagents for probing the kinin signaling system.  \u00a9 2021 Society of Chemical Industry<\/jats:p>\n                  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