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These small molecules were expected to reproduce the detrimental phenotypic effects that had been observed in <jats:italic>Rhipicephalus microplus<\/jats:italic> females when the kinin receptor was silenced by RNA interference. <jats:italic>Rhipicephalus microplus<\/jats:italic>, the southern cattle tick, cattle fever tick, or Asian blue tick, is the vector of pathogenic microorganisms causing the deadly bovine babesiosis and anaplasmosis. The widespread resistance to acaricides in tick populations worldwide emphasizes that exploring novel targets for effective tick control is imperative.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Fifty\u2010three structural analogs of previously identified tick kinin antagonists were screened in a \u2018dual\u2010addition\u2019 calcium fluorescence assay using a CHO\u2010K1 cell line expressing the tick kinin receptor. Seven molecules were validated as non\u2010cytotoxic antagonists, four of which were partial (SACC\u20100428764, SACC\u20100428780, SACC\u20100428800, and SACC\u20100428803), and three were full antagonists (SACC\u20100428799, SACC\u20100428801, and SACC\u20100428815). Four of these antagonists (SACC\u20100428764, SACC\u20100428780, SACC\u20100428799, and SACC\u20100428815) also inhibited the tick midgut contractions induced by the myotropic kinin agonist analog 1728, verifying their antagonistic bioactivity. The small molecules were tested on recombinant human neurokinin (NK) receptors, the one most similar to the invertebrate kinin receptors. Most molecules were inhibitors of the NK1 receptor, except SACC\u20100412066, a previously identified tick kinin receptor antagonist, which inhibited the NK1 receptor only at the highest concentration tested (25\u2009\u03bc<jats:sc>m<\/jats:sc>). None of the molecules inhibited the NK3 human receptor.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>Molecules identified through this approach could be useful probes for studying the tick kinin signaling system and midgut physiology. \u00a9 2024 The Author(s). <jats:italic>Pest Management Science<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Society of Chemical Industry.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ps.8242","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T05:11:32Z","timestamp":1718860292000},"page":"5168-5179","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Target\u2010based discovery of antagonists of the tick (<scp><i>Rhipicephalus microplus<\/i><\/scp>) kinin receptor identifies small molecules that inhibit midgut contractions"],"prefix":"10.1002","volume":"80","author":[{"given":"Bianca 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