L-653150

The addition of L-652,731 and L-653,150, two synthetic PAF-specific receptor antagonists, to 72 hour cultures of phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear leukocytes (PBML) caused a dose-dependent inhibition of (3H)-thymidine incorporation into T-cells (IC50: 25 microM and 3.2 microM, respectively). This inhibition was not reversed by exogenous interleukin (IL)-1 and IL-2. PAF receptor antagonists did not affect the expression of IL-2 receptors (TAC-antigen) on T-cells. Exogenous PAF which by itself had no significant effect on PHA-stimulated PBML proliferation, only partially reversed the inhibition of proliferation caused by PAF receptor antagonists. These results may suggest the involvement of endogenously produced PAF in the regulation of immune reactions.

Relative potencies of platelet activating factor (PAF) and PAF analogs and several PAF receptor antagonists when inhibiting the [3H]PAF specific binding to human and rabbit platelet membranes and membrane fragments of human lung tissues were compared. In rabbit platelets, L-652,731 was found to be most potent in the list of PAF receptor antagonists with an equilibrium inhibition constant (Ki) of 9.83 (+/- 2.92) X 10(-9) M followed by L-653,150 greater than kadsurenone congruent to Ono-6240 greater than ginkgolide B greater than CV-3988 greater than L-651,142, whereas in human platelets the relative potencies of these PAF receptor antagonists were as follows: Ono-6240 greater than L-653,150 congruent to L-652,731 congruent to kadsurenone greater than ginkgolide B greater than CV-3988 greater than L-651,142. Ono-6240 was the most potent one with a Ki of 4.86 (+/- 1.44) X 10(-8) M which was roughly two times more potent than that in rabbit platelets, whereas the affinity of L-652,731 was about ten times less in human platelets (Ki = 1.03 (+/- 0.15) X 10(-7) M) compared to that in rabbit platelets (Ki = 9.83 (+/- 2.92) X 10(-9) M). These variations between species among PAF antagonists strongly suggest that there exists a species difference at or near the binding site of the receptor of platelet activating factor. The relative potency of these PAF receptor antagonists in human lung membranes differed very little from that in human platelets and was found to be Ono-6240 greater than L-653,150 congruent to kadsurenone congruent to L-652,731 greater than ginkgolide B greater than CV-3988 greater than L-651,142. Even though C16-PAF showed slightly higher potency in human lung, and CV-3988 and Ono-6240 showed slightly lower, the difference was too small to suggest that there is a difference in the PAF receptors between human platelets and human lung tissues.