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D Aharony, CA Catanese and RC Falcone
Department of Pharmacology, ICI Pharmaceuticals Group, Wilmington, Delaware.
The specific binding of [3H]leukotriene (LT) E4 to receptors on guinea pig lung parenchymal membranes was investigated and compared to that of [3H]LTD4. [3H]LTE4 bound slower than [3H] LTD4 (k1: 0.07 +/- 0.02 nM- 1.min-1 vs. 0.13 +/- 0.01 nM-1.min-1, respectively) reaching equilibrium at lower binding levels (3-fold) than [3H]LTD4. Unlike [3H]LTD4, receptor-bound [3H]LTE4 could be rapidly (k-1 = 0.22 +/- 0.04 min-1) and fully dissociated by excess of both agonists (LTD4 and LTE4) and selective LTD4/LTE4 antagonist ICI 198,615. Equilibrium saturation analysis (paired) of specific [3H]LTE4 and [3H]LTD4 binding confirmed that [3H]LTE4 possesses lower affinity (kd values: 1.17 +/- 0.14 and 0.38 +/- 0.06 nM, respectively, n = 6, P less than .01) and lower density (maximum binding values: 524 +/- 46 and 988 +/- 66 fmol/mg, n = 6, P less than .01) binding sites. Binding of [3H]LTE4 was 3 to 4-fold more sensitive to inhibition by GTP analogs than has been demonstrated previously on [3H]LTD4. Drug competition assays illustrate that inhibition of [3H]LTE4 binding by agonists displays similar selectivity of (LTD4 greater than LTE4 much greater than LTC4) and stereoselectivity (5S,6R-LTD4 much greater than R,R greater than R,S greater than S,S) to the observed inhibition of [3H]LTD4, suggesting that [3H]LTE4 binds to LTD4 receptors. Selective LTD4 antagonists inhibited [3H]LTE4 binding with a relative potency [compound 1 (ICI 198,615 analog) greater than ICI 198,615 = ICI 204,219 greater than LTD4 greater than LTE4 much greater than FPL55712 = LY171,883] comparable to that obtained against [3H]LTD4.(ABSTRACT TRUNCATED AT 250 WORDS)
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