Disease relevance of L 659989

• Treatment with L-659,989 decreased abnormal cerebrospinal fluid cytochemical values induced by intracisternal challenge with pneumococci but not Haemophilus influenzae, indicating a special role for PAF in pneumococcal disease [1].
• Pharmacological manipulation of inflammation in rabbit hydronephrosis: effects of a combined cyclooxygenase/lipoxygenase inhibitor ethoxyquin, a thromboxane synthase inhibitor RS-5186 and a PAF antagonist L-659,989 [2].
• The cardioprotective effects of L-659,989, a specific platelet-activating factor (PAF) receptor antagonist, were investigated in an ischemia/reperfusion model in rats [3].
• Protective effects of L-659,989, a platelet-activating factor receptor antagonist, in myocardial ischemia and reperfusion in rats [3].

High impact information on L 659989

• Antibody to the CD-18 family of leukocyte adhesion molecules inhibited leukocyte recruitment in response to PAF in the brain (greater than 80%); a similar level of inhibition in the lung required treatment with a combination of a PAF receptor antagonist (L-659,989) and anti-CD18 antibody [1].
• These functions of PAF appeared to be mediated through the cell surface PAF receptors, as two PAF receptor antagonists, WEB 2086 and L-659,989, blocked both the up-regulation of HB-EGF mRNA and kappa B binding activity induced by PAF [4].
• Under certain conditions, the PAF receptor antagonist L-659,989 completely blocks the release of Ca2+ from intracellular stores, suggesting a complete block of the receptor-mediated response [5].
• Furthermore, L-659,989 (10 microM), as well as PAF (1 microM), inhibited specific [3H]PAF binding in LPS-treated but not in untreated cells [6].
• We also found that the platelet-activating factor receptor antagonists WEB 2086 and L-659,989 inhibit the oxidized LDL stimulation of PLD, suggesting a role for platelet-activating factor receptor in this process [7].

Biological context of L 659989

• Administration by mouth with L-659,989 of three concentrations (1.6, 16, and 48 mg/kg/day) did not alter the gestational period; however, the duration of parturition was increased from 2-fold to 5-fold by such treatment [8].
• IC50 values for C16-PAF, SR 27417 and other PAF receptor antagonists on all three cell types indicated that SR 27417 was at least three times more potent than C16-PAF itself and more than 30-fold as active as the best synthetic PAF receptor antagonist tested (L 659,989) [9].
• In both [3H]PAF binding and PAF-induced platelet aggregation inhibition, L-659,989 was found to be a competitive inhibitor with an equilibrium dissociation constant (KB) of 1.5 and 1.7 nM, respectively, in rabbit platelets [10].
• For 2,5-diaryl tetrahydrofurans, an unsymmetrical molecular configuration represented by the s,s-enantiomer of L-659,989 and its cyclopentane analogues is clearly preferred for optimal potency in vitro [11].
• The inhibitory effect of PAF on agonist-induced renal vasoconstriction was accentuated by eicosanoid synthesis inhibition (indomethacin or dexamethasone), unaffected by dopamine-receptor blockade (haloperidol) but was totally abolished by PAF receptor antagonism (L-659,989) [12].

Anatomical context of L 659989

• The WGA-potentiated specific binding can be specifically inhibited by N-acetylglucosamine, shows identical affinity for PAF agonists and a receptor antagonist, L-659,989, and has an identical Na+ inhibition pattern to non-treated membranes in the absence of WGA [13].
• It inhibited [3H]PAF binding to either rabbit platelet or rabbit polymorphonuclear leukocyte membranes with an equilibrium inhibition constant (Kl) of 1.1 nM; whereas in human platelet, human polymorphonuclear leukocyte or human lung membranes, L-659,989 was about 10 times less potent with a Kl of 14.3 nM [10].
• PAF (10 nM) increased intracellular free calcium concentration in human lymphocytes and this effect was inhibited by L-659,989 dose-dependently [14].
• Stably transfected fibroblasts expressing the cloned cDNA responded to sub-nanomolar PAF stimulation with calcium mobilization, which could be inhibited by the PAF antagonist L-659,989 [15].
• Utilizing an intact sheep model that involved a 90-min occlusion of the mid-left anterior descending coronary artery followed by 6 hr of reperfusion, a study group that received a specific PAF receptor antagonist (L-659,989, 5 mg/kg) 10 min before reperfusion was compared to a control group that received a saline placebo (n = 8 in each group) [16].

Associations of L 659989 with other chemical compounds

• The cytosolic free Ca2+ concentration increase was inhibited by the PAF receptor antagonist L-659,989 (10 microM) and by EGTA (2 mM), indicating receptor-dependent Ca2+ influx [6].
• The decrease in blood flow appeared to require circulating neutrophils and was prevented by dazmegral and the platelet-activating factor (PAF) antagonists WEB 2086 and L-659,989 [17].
• The 2,5-tritium labeled L-659,989, similar to [3H]PAF, specifically binds to rabbit platelet membranes with an equilibrium dissociation constant (KD) of 1.60 (+/- 0.20) nM in 10 mM MgCl2 [18].
• Because indomethacin decreases the activity of platelet-activating factor (PAF), vascular rings were treated with two different specific PAF receptor antagonists: L-659,989 and WEB 2170 BS [19].

Gene context of L 659989

• Furthermore, L-659,989 and PAF inhibited specific 3H-labeled PAF binding in TNF-treated, but not in untreated cells [20].
• Constriction to ET-1 was also blocked by the PAF antagonist L-659,989 in AA, but not EA [21].
• To evaluate the involvement of PAF in the process of parturition, we administered the PAF receptor antagonist, L-659,989, to 17-day timed pregnant rats and followed the events of labor and delivery [8].
• Treatment with L-659,989 significantly increased survival rate, blunted the rise in plasma myocardial depressant factor activity and lowered serum and macrophage levels of tumor necrosis factor (TNF-alpha) [22].
• We conclude that the use of a specific PAF receptor antagonist, L-659,989, immediately before controlled coronary reflow attenuated the activation of platelets and neutrophils that occurred during reperfusion [16].

Analytical, diagnostic and therapeutic context of L 659989

• Both BQ123 and L-659,989 completely inhibited CsA, constriction in AA, but had no significant inhibiting effect in EA [21].
• Prior to reperfusion, treated flaps received L-659,989 as in experiment 2 [23].

References