Background and purpose
The highly lipophilic acyl-sulphonamides L-798106 and L-826266 showed surprisingly slow antagonism of the prostanoid EP&sub3; 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
Purpose
The highly lipophilic acyl-sulphonamides L-798106 and L-826266 showed surprisingly slow antagonism of the prostanoid EP&sub3; 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 EP&sub3; antagonists. For ligands of low to moderate lipophilicity, potency increments for EP&sub3; and TP (thromboxane-like) agonism on guinea-pig aorta (above pEC₅&sub0; of 8.0) were associated with progressively longer onset half-times; similar trends were found for TP and histamine H&sub1; antagonism above a pA&sub2; limit of 8.0. In contrast, L-798106 (EP&sub3;), L-826266 (EP&sub3;, TP) and the lipophilic H&sub1; antagonists astemizole and terfenadine exhibited very slow onset rates despite their moderate affinities; (DG)-3ap (EP&sub3;) had a faster onset. Agonism and antagonism on the vas deferens EP&sub3; 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. EP&sub3; antagonists used as research tools should have moderate lipophilicity. The influence of lipophilicity on the potential clinical use of EP&sub3; antagonists is discussed.