Inhibition of receptor binding

Inhibition of receptor activation Inhibition of receptor binding and angiogenesis Inhibition of receptor activation... 

TABLE V Other Effects of Ca +-entry Blockers A. Inhibition of receptor binding... 

Jellmek, D., Green, L. S., Bell, C., Janjic, N. (1994). Inhibition of receptor binding by high-affinity RNA hgands to vascular endothelial growth factor. Biochemistry 33, 10450-10456. 

Ruckman, J. et al, 2 -fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain, /. Biol Chem., 273,20556,1998. 

To ensure that the inhibition of EGF binding by palytoxin was not a consequence of cell toxicity, the effect of palytoxin on DNA synthesis in Swiss 3T3 cells was monitored. When cells were incubated in the presence of palytoxin, 10% fetal calf serum, and H-thymidine for 19.5 hr, no depression in the extent of H-thymidine incorporation into DNA was detected up to 3.7 pM palytoxin (Table I). Although 11 pM palytoxin was toxic when present for a prolonged period, under the conditions of the assays described above no toxicity was detected (Table I). When cells were incubated in the presence of palytoxin, 0.1% fetal calf serum, and H-thymidine, palytoxin did not stimulate significant incorporation of H-thymidine into DNA. Thus, although it can modulate the EGF receptor system under these conditions, palytoxin alone does not appear to be mitogenic for Swiss 3T3 cells. 

Inhibition of EGF binding by palytoxin could be due to a decrease in receptor affinity, as in the case of TPA-type tumor promoters, and/or a decrease in receptor number. In Swiss 3T3 cells there are two classes of EGF receptors. The dissociation constants for the two EGF receptor classes were determined to be approximately 2 X 10 M and 2 x 10" M, corresponding to approximately 1 x 10 and 1 X 10 receptor molecules per cell, respectively (33). Scatchard analysis revealed that treatment of Swiss 3T3 cells with palytoxin, like PDBu, caused an apparent loss in high-affinity binding (Figure 2). However, in contrast to PDBu, palytoxin also caused a significant (approximately 50%) loss of low affinity EGF binding. 

Because these results suggest that extracellular Na is required for inhibition of EGF binding by palytoxin in these cells, we determined if palytoxin caused Na influx in Swiss 3T3 cells. When Na influx was monitored at an early time point (7 min), it was found that palytoxin causes an influx of Na and that the rate of Na influx is dose dependent (Figure 6). In parallel with its effect on EGF binding, palytoxin at different doses increases intracellular Na to the same final level (42). Although Na influx occurs prior to the inhibition of EGF binding, these results and the apparent Na dependence of the palytoxin effect suggest a role for Na in the action of palytoxin on the EGF receptor. 

TABLE 1. Drug inhibition of specific binding of various 3H-ligands to sigma and PCP receptor sites in brain... 

Stereoselectivity was evident in the assays for stereotyped behavior and PCP receptor interaction, but not in the assay for ataxia as the (+) isomers of the PCP-like drugs and SKF-10,047 were more potent than the (-) isomers in induction of stereotyped behavior and inhibition of binding of 3H-PCP. However, one exception to this trend is that the (-) isomer of cyclazocine was more potent than the (+) isomer in industion of stereotyped behavior and inhibition of the binding of 3H-PCP. 

Inhaled corticosteroids are the preferred long-term control therapy for persistent asthma in all patients because of their potency and consistent effectiveness they are also the only therapy shown to reduce the risk of death from asthma. Comparative doses are included in Table 80-3. Most patients with moderate disease can be controlled with twice-daily dosing some products have once-daily dosing indications. Patients with more severe disease require multiple daily dosing. Because the inflammatory response of asthma inhibits steroid receptor binding, patients should be started on higher and more frequent doses and then tapered down once control has been achieved. The response to inhaled corticosteroids is delayed symptoms improve in most patients within the first 1 to 2 weeks and reach maximum improvement in 4 to 8 weeks. Maximum improvement in FEVj and PEF rates may require 3 to 6 weeks. 

A paper detailing the properties of the multikinase inhibitor ABT-869 (7) did not indicate whether plasma protein binding data were used in the optimization leading to this highly protein-bound (mouse 98.2%, human 99.0%) compound [45]. A dose which provided a 69% reduction in tumor growth and >50% inhibition of receptor phosphorylation and pharmacodynamic response afforded plasma concentration that remained above the cellular IC50 for receptor phosphorylation in the presence of plasma for 4 of 12 h in the bid dosing cycle. 

It is interesting that, in addition to its AChE inhibitory eflfects, huperzine A is reported to inhibit NMDA receptor binding and this is also of use in treating AD/ Recently, three compounds, huprine X (42) and its F and Br analogues, huprine Y and huprine Z have been synthesized. These compounds combine the carbobicyclic structural feature of huperzine A (40) with the 4-aminoquinoline skeleton of tacrine (28). All three compounds showed a very strong selectivity for AChE over BuChE and also for human as opposed to bovine AChE and this was demonstrated in vivo as well as in vitro. 

Infliximab neutralizes the biological activity of tumor necrosis factor alpha (TNF ) by high-affinity binding to its soluble and transmembrane forms and inhibits TNF receptor binding. Infliximab does not neutralize TNF (lymphotoxin ), a related cytokine that uses the same receptors as TNF . 

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