Assessment of leukotriene D4 receptor antagonists.
Both [3H]LTD4 and [3H]ICI 198,615 bind selectively and with high affinity to LTD4 receptors on guinea pig and human lung membranes. Binding is inhibited by selective LTD4 antagonists. However there may be some advantages for preferring one over the other, which is largely due to the specific experimental design. For example, due to the apparent higher affinity of agonists in the [3H]LTD4 binding assay, one can use this ligand to measure competition by agonists, partial agonists, and to determine the stereoselectivity of LTD4 analogs. The disadvantages are susceptibility to oxidation, double-bond isomerization under acidic condition, metabolism by membrane aminopeptidase, and requirement for optimization of "agonist binding conditions" that may limit the use of this ligand in different tissues (i.e., ileum or brain). [3H]ICI 198,615 does not suffer from these disadvantages and allows the direct determination of potency for structurally diverse antagonists without the necessity to optimize the assay for agonist binding. An additional advantage is the ability to distinguish between agonists and antagonists at the receptor binding level, since only agonists inhibition curves (against [3H]ICI 198,615) are shifted to lower affinity by stable GTP analogs. However, one has to bear in mind that although these binding assays are highly efficient, rapid, and possess high capacity to test antagonist potency and mechanism, they do not provide broad pharmacological information as do functional receptor assays that utilize viable tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
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D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D006168:Guinea Pigs; D007191:Indazoles / Q000378:metabolism*; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D008297:Male; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
D007191:Indazoles; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C054217:ICI 198615