Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations

RL Jones, DF Woodward, JW Wang… - British journal of …, 2011 - Wiley Online Library
RL Jones, DF Woodward, JW Wang, RL Clark
British journal of pharmacology, 2011Wiley Online Library
BACKGROUND AND PURPOSE The highly lipophilic acyl‐sulphonamides L‐798106 and L‐
826266 showed surprisingly slow antagonism of the prostanoid EP3 receptor system in
guinea‐pig aorta. Roles of affinity and lipophilicity in the onset kinetics of these and other
prostanoid ligands were investigated. EXPERIMENTAL APPROACH Antagonist selectivity
was assessed using a panel of human recombinant prostanoid receptor‐fluorimetric
imaging plate reader assays. Potencies/affinities and onset half‐times of agonists and …
BACKGROUND AND PURPOSE The highly lipophilic acyl‐sulphonamides L‐798106 and L‐826266 showed surprisingly slow antagonism of the prostanoid EP3 receptor system in guinea‐pig aorta. Roles of affinity and lipophilicity in the onset kinetics of these and other prostanoid ligands were investigated.
EXPERIMENTAL APPROACH Antagonist selectivity was assessed using a panel of human recombinant prostanoid receptor‐fluorimetric imaging plate reader assays. Potencies/affinities and onset half‐times of agonists and antagonists were obtained on guinea‐pig‐isolated aorta and vas deferens. n‐Octanol‐water partition coefficients were predicted.
KEY RESULTS L‐798106, L‐826266 and the less lipophilic congener (DG)‐3ap appear to behave as selective, competitive‐reversible EP3 antagonists. For ligands of low to moderate lipophilicity, potency increments for EP3 and TP (thromboxane‐like) agonism on guinea‐pig aorta (above pEC50 of 8.0) were associated with progressively longer onset half‐times; similar trends were found for TP and histamine H1 antagonism above a pA2 limit of 8.0. In contrast, L‐798106 (EP3), L‐826266 (EP3, TP) and the lipophilic H1 antagonists astemizole and terfenadine exhibited very slow onset rates despite their moderate affinities; (DG)‐3ap (EP3) had a faster onset. Agonism and antagonism on the vas deferens EP3 system were overall much faster, although trends were similar.
CONCLUSIONS AND IMPLICATIONS High affinity and high liphophilicity may contribute to the slow onsets of prostanoid ligands in some isolated smooth muscle preparations. Both relationships are explicable by tissue disposition under the limited diffusion model. EP3 antagonists used as research tools should have moderate lipophilicity. The influence of lipophilicity on the potential clinical use of EP3 antagonists is discussed.
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