12 (R)-METHYL-LEUKOTRIENE-B(3) - A STABLE LEUKOTRIENE B ANALOG TOWARDTHE REDUCTASE METABOLISM

Biological potencies of 12(Runderbar)-methyl-LTB3 [12(Runderbar)-Me-LT B3] and 12(Sunderbar)-Me-LTB3 and their stability toward reductase met abolism are described. 12(Runderbar)- and 12(Sunderbar)-Me-LTB3 of mor e than 95% chemical purity were synthesized highly stereoselectively v ia the palladium catalyzed coupling reaction of the vinylborane derive d from the enyne 1 and Sia2BH with the iodide 2 of Runderbar and Sunde rbar configuration. To assess biological activity of 12-Me-LTB3, cytos olic free calcium ([Ca2+]iunderbar) rise in rat PMNLs and binding affi nity to the LTB4 receptors were compared with those of natural LTB4. T he potency of 12(Runderbar)-Me-LTB3 was found to be almost equal to LT B4, while, by complete contrast, 12(Sunderbar) isomer showed very low activity of 1/200 - 1/400. These results indicate that the C(12) hydro xyl group of Runderbar configuration is essential to elicit the biolog ical activity and that [Ca2+]iunderbar rise elicited by 12-Me-LTB3 is mediated through interaction with the LTB4 receptors. Stability of 12( Runderbar)-Me-LTB3 toward the reductase metabolism was evaluated by us ing rat PMNLs. Thus, rat PMNLs were incubated at 37-degrees-C with 12( Runderbar)-Me-LTB3 and LTB4, respectively. The amount of 12(Runderbar) -Me-LTB3 was almost unchanged up to 30 min under these conditions, tho ugh LTB4 was rapidly consumed in a time-dependent manner, thus strongl y indicating that 12(Runderbar)-Me-LTB3 is not metabolized via the red uctase pathway.