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Biomedical subjects

S B Hwang

Publications and source records attributed to S B Hwang.

At least 55 records · Page 3Linked to original sources
PubMed1988

Biochemical and pharmacological characterization of L-659,989: an extremely potent, selective and competitive receptor antagonist of platelet-activating factor.

L-659,989 [trans-2-(3-methoxy-5-methylsulfonyl-4-propoxy-phenyl)-5-(3,4,5- trimethoxyphenyl)tetrahydrofuran] is a p.o. active and extremely potent, selective and competitive platelet-activating factor (PAF) receptor antagonist. 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. The structural specificity of L-659,989 was demonstrated by the low activity of its cisisomer which was about 100 to 200 times less potent, also the (-)-L-659,989 was found to be 20- to 30-fold more potent than (+)-L-659,989. 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. Even up to 6 microM concentration, L-659,989 showed no inhibition on the aggregation of rabbit platelets in plasma induced by ADP, arachidonic acid, collagen or thrombin. In an in vivo model, it inhibited guinea pig bronchoconstriction induced by i.v. infusion of 75 ng/kg of PAF with ED50 values of 13 micrograms/kg i.v. and 0.5 mg/kg p.o.

Animals↗
PubMed1987

L-652,469--a dual receptor antagonist of platelet activating factor and dihydropyridines from Tussilago farfara L.

L-652,469, 14-acetoxy-7 beta-(3'-ethylcrotonoyloxy)-notonipetranone, isolated from the methylene chloride extracts of the buds of Tussilago farfara L, was found to inhibit both platelet activating factor (PAF) and Ca2+ entry blocker binding to membrane vesicles. It inhibits the [3H]PAF specific binding to rabbit platelet membranes with equilibrium inhibition constants (Ki) of 3.2 and 4.0 microM in the presence of 150 mM NaCl and 10 mM MgCl2 respectively. It is a competitive PAF receptor antagonist with an equilibrium dissociation constant (KB) of 5.16 microM. It also competitively inhibits the specific binding of Ca2+ channel blockers (e.g. [3H]nitrendipine; Ki = 1.2 microM) in cardiac sarcolemmal vesicles. At 10(-5) M, L-652,469 causes a 60% relaxation of Ca2+-induced contraction of rat thoracic aorta strips. Due to its dual antagonistic activities, L-652,469 potently inhibits the gel-filtered rabbit platelet aggregation with a pA2 of 5.79. It was also found to be orally active with a beneficial effect to inhibit the PAF-induced rat foot edema and the first phase of carrageenan-induced rat hindpaw edema.

Animals↗
PubMed1987

Specific receptor sites for platelet activating factor on rat liver plasma membranes.

The binding of 3H-labeled 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine (PAF) to isolated rat liver plasma membranes and its inhibition by PAF agonists and receptor antagonists was demonstrated. The specific binding was readily saturable with a high affinity. The equilibrium dissociation constant (KD) value was 0.51 (+/- 0.14) nM and the maximal number of binding sites (Bmax) was estimated to be 141 (+/- 18) fmol/mg protein. The binding site was PAF specific-biologically inactive enantiomer was practically inactive. Two PAF-like receptor antagonists, Ono-6240 and CV-3988, and two PAF-unlike receptor antagonists, L-652,731 and kadsurenone, also displaced the binding of [3H]PAF to rat liver plasma membranes but their relative potencies in this system differed from those found in other receptor systems. Mg2+ potentiated [3H]PAF binding but inhibited it at concentrations higher than 10 mM. Both Na+ and K+ inhibited the Mg2+-potentiated binding, an ionic effect which was different from that found in rabbit platelets. These results suggest that rat livers contain PAF-specific receptors, and the receptors in rat livers are different from those found in other receptor systems.

Alkaline Phosphatase↗
PubMed1987

Structure-activity relationships of kadsurenone analogues.

Kadsurenone, a specific receptor antagonist of platelet-activating factor (PAF), and its analogues were prepared from derivatives of cinnamyl alcohol and (allyloxy)phenol. Racemic kadsurenone, resolvable by a Chiralpak column at low temperatures, has an IC50 value of 2 X 10(-7) M, which is about 50% of the activity of the natural product (IC50 = 1 X 10(-7) M). The structural specificity of kadsurenone was further demonstrated by the low PAF-receptor-blocking activities of denudatin B, mirandin A, desallylkadsurenone, and the 2-epimer of kadsurenone.

Animals↗
PubMed1986

Species difference in the specific receptors of platelet activating factor.

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.

Animals↗
PubMed1986

Specific binding of [3H]dihydrokadsurenone to rabbit platelet membranes and its inhibition by the receptor agonists and antagonists of platelet-activating factor.

Kadsurenone inhibits specifically and competitively the specific binding of 3H-labeled platelet-activating factor ([3H]PAF) to rabbit platelet membranes. Since the 5-propyl analog of kadsurenone (dihydrokadsurenone) retains roughly the same potency as kadsurenone, [3H]dihydrokadsurenone was therefore synthesized through tritiation of kadsurenone. Specific binding of [3H]dihydrokadsurenone in rabbit platelet membranes is saturable. Scatchard analysis of binding data reveals the presence of a single class of binding sites with an equilibrium dissociation constant (KD) of 16.81 ( +/- 0.57) nM. The total number (Bmax) of detectable binding sites is 2.27 ( +/- 0.09) pmol/mg protein. Both C16- and C18-PAF fully displace the specific binding of (3H]dihydrokadsurenone (5 nM) with an identical ED50 of 3.6 X 10(-9) M. Dihydrokadsurenone and kadsurenone also displace the specific binding with roughly the same potency (ED50 = 4.4 X 10(-8) M). Several other PAF analogs and PAF receptor antagonists tested show relative potencies roughly similar to those found in the [3H]PAF-specific binding assay. Other pharmacological agents with no PAF antagonistic activities did not inhibit the specific binding of [3H]dihydrokadsurenone. These results agree with our previous conclusion that kadsurenone is a specific and competitive receptor antagonist and strongly suggest that PAF and the PAF receptor antagonists tested may interact at a common binding site in the PAF receptor.

Animals↗
PubMed1986

Ionic and GTP regulation of binding of platelet-activating factor to receptors and platelet-activating factor-induced activation of GTPase in rabbit platelet membranes.

Specific binding of 3H-labeled platelet-activating factor (PAF) to rabbit platelet membranes was found to be regulated by monovalent and divalent cations and GTP. At 0 degrees C, inhibition of [3H]PAF binding by sodium is specific, with an ED50 of 6 mM, while Li+ is 25-fold less effective. On the contrary, K+, Cs+, and Rb+ enhance the binding. The divalent cations, Mg2+, Ca2+, and Mn2+ enhance the specific binding 8-10-fold. From both Scatchard and Klotz analyses, the inhibitory effect of Na+ is apparently due to an increase in the equilibrium dissociation constant (KD) of PAF binding to its receptors. However, the Mg2+-induced enhancement of the PAF specific binding may be attributed to an increased affinity of the receptor and an increased availability of the receptor sites. In the presence of Na+, PAF receptor affinity decreased with increasing temperature with a 100-fold sharp discontinuous decrease in receptor affinity at 24 degrees C. In contrast, the Mg2+-induced increase is independent of temperature suggesting that the Mg2+ regulatory site is different from Na+ regulatory site. [3H]PAF binding is also specifically inhibited by GTP; other nucleotides have little effect. PAF also stimulates hydrolysis of [gamma-32P]GTP with an ED50 of 0.7 nM, whereas 3-O-hexadecyl-2-O-acetyl-sn-glyceryl-1-phosphorylcholine showed no activity even at 10 microM. Moreover, such stimulatory effect of PAF is dependent on Na+ and can be abolished by the PAF-specific receptor antagonist, kadsurenone, but not by an inactive analog, kadsurin B. These results suggest that the PAF receptor may be coupled with the adenylate cyclase system via an inhibitory guanine nucleotide regulatory protein.

Animals↗
PubMed1986

Release of platelet activating factor and its involvement in the first phase of carrageenin-induced rat foot edema.

Platelet activating factor (PAF), a potent lipid-like vasoactive agent, induced rat foot edema when it was injected subplantarly. The edema reached its maximum 1 h after PAF challenge. Indomethacin did not inhibit the peak edematous response whereas both PAF antagonists, kadsurenone and L-652,731, inhibit the PAF-induced rat foot edema (PFE). Both PAF antagonists also partially block the first phase of the carrageenin-induced rat foot edema (CFE). Using the inhibition of [3H]PAF receptor binding to prepared rabbit platelet membranes, release of PAF or PAF-like materials in carrageenin-injected rat hindpaw was observed. These results suggest that the released PAF or PAF-like materials together with the released histamine and kinin evoke the first phase hindpaw edema in the rats. Indomethacin or PAF antagonist, administered alone, does not block the first phase or the second phase of CFE, respectively. However, PAF antagonist potentiated the inhibitory effects of indomethacin suggesting that the released PAF may also be involved in the biosynthesis of prostaglandins to initiate the second phase of rat CFE.

Animals↗
PubMed1986

Conformation and activity of tetrahydrofuran lignans and analogues as specific platelet activating factor antagonists.

The six (racemic or meso) isomers of 3,4-dimethyl-2,5-bis(3,4-dimethoxyphenyl)tetrahydrofuran and four corresponding desmethyl analogues were prepared and assayed as inhibitors of platelet activating factor (PAF) receptor binding to rabbit platelet plasma membranes. The inhibition by these isomers is stereodependent and varies with the gross shape of the molecules as determined by the molecular mechanics program MM2. The most potent PAF antagonist in this group of compounds is trans-2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-652,731, 14) with an IC50 of 0.02 microM.

Animals↗
PubMed1985

trans-2,5-Bis-(3,4,5-trimethoxyphenyl)tetrahydrofuran. An orally active specific and competitive receptor antagonist of platelet activating factor.

trans-2,5-Bis(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-652,731) is found to be a potent and orally active platelet activating factor (PAF)-specific and competitive receptor antagonist. It potently inhibits [3H]PAF (1 nM) binding to receptor sites on rabbit platelet membranes with an ED50 of 2 X 10(-8) M under the assay condition without the addition of mono- or divalent cations. In a comparative study, it is more potent than CV-3988, kadsurenone, and ginkgolide B as a receptor antagonist. The equilibrium dissociation constants (KB) of L-652,731 obtained either from the inhibition of receptor binding or from the inhibition of PAF-induced aggregation of gel-filtered rabbit platelet are 2.7 X 10(-8) and 2.1 X 10(-8) M, respectively. The agreement of these KB determinations based on receptor and cellular function suggests that L-652,731 does not inhibit other steps following PAF-receptor binding. L-652,731 does not antagonize the binding of several radioligands to their respective receptor. It shows no inhibitory effect on platelet aggregation induced by other aggregating agents including thrombin, collagen, A-23187, arachidonic acid, epinephrine, and ADP. L-652,731 is orally active; it inhibits PAF-induced rat cutaneous vascular permeability with an ED50 of 30 mg/kg orally. Significant inhibitory results of L-652,731 suggest that PAF may be partially involved in cutaneous vascular permeability induced by histamine and bradykinin.

Animals↗
PubMed1985

Specific binding sites for platelet activating factor in human lung tissues.

Specific and saturable binding of [3H]-labeled 1-0-alkyl-2-0-acetyl-sn-glycero-3-phosphocholine (PAF) to membrane preparations of human lung tissues is demonstrated. The equilibrium dissociation constant (KD) was determined by Scatchard analysis to be 4.9 (+/- 1.7) X 10(-10)M and the maximal number of binding sites was estimated to be 140 (+/- 37) fmole/mg protein. The binding site is PAF specific and its selectivity toward PAF analogs is very similar to that in rabbit platelets. Two PAF receptor antagonists, kadsurenone and ginkgolide B, previously characterized in platelet systems, also displace the binding of [3H]-PAF to human lung homogenates. These data indicate that human lung tissues contain PAF specific receptors, and binding of PAF to these receptor sites may be the first step to initiate PAF-induced lung pathophysiology.

Binding Sites↗
PubMed1985

Characterization of a platelet-activating factor receptor antagonist isolated from haifenteng (Piper futokadsura): specific inhibition of in vitro and in vivo platelet-activating factor-induced effects.

Platelet-activating factor (PAF) is a potent lipid mediator of inflammation and asthma. Using a receptor preparation of rabbit platelet membranes, we identified a novel antagonist of PAF in the methylene chloride extract of a Chinese herbal plant, haifenteng (Piper futokadsura). The active antagonist, kadsurenone, was isolated and characterized in several in vitro and in vivo assays. It is a specific and competitive inhibitor of PAF binding to its receptor with a Ki of 5.8 X 10(-8) M vs. a Ki of 6.3 X 10(-9) M for PAF itself. It inhibits PAF-induced aggregation of rabbit platelets and human neutrophils at 2.4-24 microM, without showing any PAF agonistic activity. It potently inhibits PAF-induced degranulation of human neutrophils at 2.5-50 microM, also without any agonist activity. Kadsurenone is active orally at 25-50 mg/kg of body weight in blocking PAF-induced cutaneous permeability in the guinea pig. It also inhibits PAF-induced increases of hematocrit and circulating N-acetylglucosaminidase in the rat at greater than 10 mg/kg i.p. in a dose-dependent manner. Kadsurenone does not interfere with the function of several pharmacological mediators and receptors tested. Its structural specificity is evidenced by the poor PAF-antagonistic activities of three related structures isolated from the same haifenteng extract.

Animals↗
PubMed1985

The isolation and characterization of kadsurenone from haifenteng (Piper futokadsura) as an orally active specific receptor antagonist of platelet-activating factor.

A natural product, kadsurenone, was isolated from the Chinese herbal preparation haifenteng (Caulis piperis futokadsurae) and characterized as an orally-active specific antagonist of the platelet-activating factor (PAF). Kadsurenone inhibits the specific binding of 3H-PAF to a receptor preparation from rabbit platelet membrane in a competitive and reversible manner, its Ki being 3.88 X 10(-8) M. It inhibits the aggregation of rabbit platelets in plasma induced by PAF with a pA2 of 6.28, but not those induced by arachidonic acid, epinephrine, ADP or A-23187. It inhibits the aggregation of isolated human neutrophils with a pA2 of 6.32. It also inhibits PAF-induced degranulation and release of beta-D-glucuronidase at 2-24 microM in vitro. In the rat, kadsurenone at 8-40 mg/kg i.p. inhibits the increases of plasma lysosomal enzymes and haematocrit induced by intravenous PAF. In the guinea pig, kadsurenone at 25-50 mg/kg p.o. reduces the increase of cutaneous vascular permeability induced by PAF. These results indicate that kadsurenone is a specific and effective receptor antagonist of PAF in several in vitro and in vivo systems.

Animals↗
PubMed1985

Characterization of cutaneous vascular permeability induced by platelet-activating factor in guinea pigs and rats and its inhibition by a platelet-activating factor receptor antagonist.

Mechanisms of platelet-activating factor (PAF)-induced increases of cutaneous vascular permeability in guinea pigs and in rats were further explored. PAF so far is the most potent vasoactive mediator, being more than 1000-fold more potent than histamine and bradykinin in both species. In guinea pigs, there is a time delay of 5 to 10 minutes before PAF action, whereas, in the rat, the increased vasopermeability occurs immediately following the intradermal PAF injection. Relative vasoactive potencies of PAF and several structure-related analogues in both species correlate very well with their relative inhibition of the binding of 3H-PAF to specific receptor sites on isolated rabbit platelet plasma membranes and their aggregatory abilities of rabbit platelets. Furthermore, the PAF-induced cutaneous vascular permeability is inhibitable by a competitive specific PAF receptor antagonist, kadsurenone, suggesting that binding of PAF to its specific receptor site is the first step to initiate its action of increased cutaneous vascular permeability. Several pure cyclooxygenase inhibitors, including indomethacin, diflunisal, and flurbiprofen, and the dual cyclooxygenase/lipoxygenase inhibitor, BW755C, but not the histamine antagonists, inhibit the PAF-induced vasopermeability in guinea pigs. The inhibition by indomethacin or BW755C can be fully reversed by coinjection intradermally with PAF and prostaglandin E1 but not leukotriene B4. Also, prostaglandin E1 but not leukotriene B4 enhances the guinea pig in vivo response to PAF in this model. However, in rats, none of the cyclooxygenase inhibitors, histamine antagonists, or BW755C inhibit the PAF effect of cutaneous phenomena even though prostaglandin E1 also enhances the PAF potency of the increased cutaneous vascular permeability. Kadsurenone, a competitive specific receptor antagonist, inhibits both histamine- and bradykinin-induced rat cutaneous vascular permeability which suggests that PAF may be involved in the vasopermeability induced by histamine and bradykinin.

Animals↗
PubMed1984

Effects of nonsteroid antiinflammatory drugs on the specific binding of platelet activating factor to membrane preparations of rabbit platelets.

The inhibitory effects of several antiinflammatory agents on the specific binding of tritiated 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine, (platelet activating factor, PAF), with its receptor on isolated rabbit platelet plasma membranes were investigated. Several potent cyclooxygenase inhibitors do not inhibit 3H-PAF binding to its receptor sites. Yet, three others, indomethacin, phenylbutazone and sulfinpyrazone, as well as three non-cyclooxygenase inhibitors, the 3',4'-dimethoxy analog of indomethacin, the prodrug sulindac and its sulfone metabolite, are moderately active at relatively high concentrations (50 - 100 microM). Parallel inhibitions of 3H-PAF binding and PAF-induced platelet aggregation by derivatives of these antiinflammatory agents suggest that these inhibitors are probably interacting with the functional binding sites of PAF. The results clearly indicate that the configuration of PAF binding site is very different from the inhibitory site of cyclooxygenase. A preference for oxygenated substituents in these hydrophobic molecules to inhibit the PAF-receptor binding is noted. Some binding characteristics of the receptor are briefly discussed.

Animals↗
PubMed1983

Specific receptor sites for 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine (platelet activating factor) on rabbit platelet and guinea pig smooth muscle membranes.

By using tritiated 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine (3H-PAF), we have directly identified its specific binding sites on rabbit platelet plasma membranes. The equilibrium dissociation constant for 3H-PAF is 1.36 (+/- 0.05) X 10(-9) M at 0 degrees C. The number of binding sites is 1.61 (+/- 0.34) X 10(12)/mg of membrane, which corresponds to approximately 150-300 receptors/platelet (depending on membrane vesicle orientation). Binding of 3H-PAF to rabbit platelet plasma membrane is rapid (t1/2 less than 5 min at 0 degrees C) and reversible. For a series of PAF analogues, their affinity for the receptor sites parallels with their relative potency to induce platelet aggregation. PAF can cause contraction of smooth muscle of heart, parenchymal strip, trachea, and ileum. Specific PAF receptor binding was demonstrated with purified plasma membrane from several smooth muscles and from polymorphonuclear leukocytes but not from presumably PAF nonresponsive cells such as erythrocytes and alveolar macrophages. It is likely that the interaction of PAF with these binding sites initiates the specific responses of platelets, polymorphonuclear leukocytes, and smooth muscles.

Animals↗