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Pharmacological Characterization of Kappa Opioid Receptor Agonists
Author(s) -
Kaska Sophia,
Kornberger Lindsay,
Biggerstaff Andrew,
Kivell Bronwyn,
Prisinzano Thomas
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.663.14
Subject(s) - analgesic , pharmacology , κ opioid receptor , dysphoria , in vivo , agonist , opioid , receptor , potency , chemistry , medicine , in vitro , biology , biochemistry , anxiety , microbiology and biotechnology , psychiatry
Agonists of the kappa opioid receptor (KOR) demonstrate promise for treating pain without the typical side effects of mu opioid receptor agonists, such as respiratory depression and tolerance. Unfortunately, KOR agonists have their own side effects such as sedation and dysphoria, which necessitates further development of new KOR agonists that will maintain analgesic effects while eliminating these negative side effects. Through structure‐activity relationship studies, our laboratory has identified a series of potent and selective KOR agonists that demonstrate functional selectivity for the G‐protein pathway, increasing the propensity to display analgesic effects with fewer side effects that are mediated through beta‐arrestin. Furthermore, in vivo evaluation of the analgesic effects of these compounds demonstrated an increase in potency, compared to U50,488, consistent with our in vitro data. To further demonstrate the analgesic effects of our compounds, a time course experiment was performed using the hot water tail flick assay. Over this time course, these analogs at lower doses demonstrated the same efficacy compared to U50,488, indicating an increase in analgesic effect of these compounds. Together, these data demonstrate that our series of KOR agonists have improved in vitro and in vivo activity compared to U50,488 and can potentially be used for treating pain. Support or Funding Information This work was supported by NIH R01 DA018151 and the Health Research Council of New Zealand. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .