Pharmacodynamic relationships between duration of action of jdtic-like kappa-opioid receptor antagonists and their brain and plasma pharmacokinetics in rats
JDTic is a potent and selective kappa-opioid receptor (KOR) antagonist that reverses U50,488-induced diuresis in rats. It partitions into brain with a duration of action lasting for weeks. In a search for KOR antagonists that do not accumulate in the brain, we compared single doses of five methylated JDTic analogs (RTI-97, -194, -212, -240, and -241) for reversal of U50,488 diuresis and pharmacokinetic (PK) properties. All six compounds showed potent and selective KOR antagonism in a [S-35]GTP gamma S binding assay. Plasma half-lives ranged from 24 to 41 h and brain half-lives from 24 to 76 h. JDTic and RTI-194 showed increasing brain to plasma ratios over time, indicating increasing partitioning into brain and a longer duration of action for reversal of diuresis than did RTI-97. RTI-240 did not show significant brain accumulation. RTI-212 showed no substantive difference between brain and plasma levels and was inactive against diuresis. RTI-241, with a lower brain to plasma ratio than JDTic and RTI-194, formed JDTic as a metabolite, which still reduced diuresis after 9 weeks. The fact that the duration of action was correlated with the brain to blood plasma ratios and area under the concentration-time curves suggests that PK properties could help to predict safety and acceptable duration of action for KOR antagonists.
Owens, S. M., Pollard, G. T., Howard, J. L., Fennell, T. R., Snyder, R. W., & Carroll, F. I. (2016). Pharmacodynamic relationships between duration of action of jdtic-like kappa-opioid receptor antagonists and their brain and plasma pharmacokinetics in rats. ACS Chemical Neuroscience, 7(12), 1737-1745. https://doi.org/10.1021/acschemneuro.6b00249