title: Comparison of antagonist and agonist binding to the leukotriene B4 receptor intact human polymorphonuclear neutrophils (PMN).
abstract: In the present studies, the pharmacology of the leukotriene B4 (LTB4) receptor on intact human polymorphonuclear neutrophils (PMN) was characterized using radioligand binding techniques with [3H]LTB4 and a novel LTB4 receptor antagonist radioligand [3H]CGS 23131 (LY223982). Saturation studies revealed that [3H]CGS 23131 labeled a single class of recognition sites with high affinity (Kd = 13 nM) and limited capacity (apparent Bmax = 2.8 pmol/10(7) cells). In contrast, [3H]LTB4 labeled both a set of high (Kd = 0.3 nM) and lower affinity (Kd = 5 nM) recognition sites. However, the apparent density of [3H]LTB4 binding to intact human PMN (combined Bmax = 380 fmol/10(7) cells) was approximately 14% of that observed with [3H]CGS 23131. In ligand competition studies, various LTB4 agonists and antagonists were found to inhibit the binding of [3H]CGS 23131, revealing a pharmacological profile consistent with the specific labeling of the LTB4 receptor. A positive rank order correlation (r = 0.79) was observed between the ligand competition profiles obtained with [3H]CGS 23131 and [3H]LTB4. Both LTB4 and its omega oxidation product, 20-OH-LTB4, were found to inhibit the binding of 1.0 nM [3H]CGS 23131 in a biphasic fashion consistent with the existence of multiple affinity components of the LTB4 receptor. In competing for 0.5 nM [3H]LTB4 binding, these compounds were found to produce monophasic inhibition curves, which was indicative of a selective interaction at the high-affinity LTB4 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Research Department, CIBA-GEIGY Corporation, Summit, New Jersey.
authors.forename: R H
authors.initials: RH
authors.lastname: Jackson
authors.forename: M M
authors.initials: MM
authors.lastname: Morrissey
authors.forename: M A
authors.initials: MA
authors.lastname: Sills
authors.forename: M F
authors.initials: MF
authors.lastname: Jarvis
mesh_terms: D001577:Benzophenones / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D004347:Drug Interactions; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D015289:Leukotrienes / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism*; D018102:Receptors, Leukotriene B4
chemical_list: D001577:Benzophenones; D015289:Leukotrienes; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; C065916:LY 223982; D007975:Leukotriene B4