Potent Platelet-activating Factor Research Articles

Identification and In Silico Simulation on Inhibitory Platelet-Activating Factor Acetyl Hydrolase Peptides from Dry-Cured Pork Coppa

The unique processing technology of dry-cured meat products leads to strong proteolysis, which produces numerous peptides. The purpose of this investigation was the systematic isolation, purification, and identification of potentially cardioprotective bioactive peptides from dry-cured pork coppa during processing. According to the results of anti-platelet-activating factor acetyl hydrolase activity and radical scavenging ability in vitro, the inhibitory effect of M1F2 in purified fractions on cardiovascular inflammation was higher than that of M2F2. The peptide of M1F2 was identified by nano-liquid chromatography-tandem mass spectrometry. A total of 30 peptides were identified. Based on bioinformatics methods, including in silico analysis and molecular docking, LTDKPFL, VEAPPAKVP, KVPVPAPK, IPVPKK, and PIKRSP were identified as the most promising potential platelet-activating factor acetyl hydrolase inhibitory peptides. Overall, bioactive peptides produced during dry-cured pork coppa processing demonstrate positive effects on human health.

Substituted pyridine-quinoline ligands as building blocks for neutral rhodium(III) complexes. Synthesis, structural characterization studies and anti-platelet activity towards the Platelet-Activating Factor (PAF)

The Friedländer condensation reaction was employed to synthesize the new bidentate ligands namely 6-bromo-4-phenyl-2-pyridin-2-yl-quinoline (1) and 4-(4-phenyl-2-(pyridin-2-yl)quinolin-6-yl)phenol (2). These compounds were fully characterized including the X-ray structures of 1 and the protonated form of 2, i.e. 2·HCl·H2O. We also report the synthesis and spectroscopic characterization of two rhodium(III) complexes of the general formula [Rh(1)Cl3(CH3OH)] (3) and [Rh(2)Cl3(CH3OH)] (4). The molecular structures of 3·2CH3OH and 4 were determined by single-crystal X-ray diffraction studies, revealing that these complexes adopt the mer-configuration. The solution stability of 3, 4 was studied by a combination of UV–Vis and 1H NMR spectroscopic techniques. All compounds were biologically evaluated for their anti- platelet activity using their potency to inhibit the action of PAF (Platelet-Activating Factor), which is an approach of continuous interest in the field. Complexes 3 and 4 were found to be potent PAF inhibitors with IC50 values in the micromolar range (1.0 μM and 3.9 μM respectively). Since PAF is the most potent inflammatory lipid mediator, the PAF-inhibitors and consequently the title compounds may be considered as potent examples in the search for novel anti-inflammatory drugs.

Modulation of inflammatory platelet-activating factor (PAF) receptor by the acyl analogue of PAF

Platelet-activating factor (PAF) is a potent inflammatory mediator that exerts its actions via the single PAF receptor (PAF-R). Cells that biosynthesize alkyl-PAF also make abundant amounts of the less potent PAF analogue acyl-PAF, which competes for PAF-R. Both PAF species are degraded by the plasma form of PAF acetylhydrolase (PAF-AH). We examined whether cogenerated acyl-PAF protects alkyl-PAF from systemic degradation by acting as a sacrificial substrate to enhance inflammatory stimulation or as an inhibitor to dampen PAF-R signaling. In ex vivo experiments both PAF species are prothrombotic in isolation, but acyl-PAF reduced the alkyl-PAF-induced stimulation of human platelets that express canonical PAF-R. In Swiss albino mice, alkyl-PAF causes sudden death, but this effect can also be suppressed by simultaneously administering boluses of acyl-PAF. When PAF-AH levels were incrementally elevated, the protective effect of acyl-PAF on alkyl-PAF-induced death was serially decreased. We conclude that, although acyl-PAF in isolation is mildly proinflammatory, in a pathophysiological setting abundant acyl-PAF suppresses the action of alkyl-PAF. These studies provide evidence for a previously unrecognized role for acyl-PAF as an inflammatory set-point modulator that regulates both PAF-R signaling and hydrolysis.

Tetrahydrobenzofuran-6(2 H)-one Neolignans from Ocotea heterochroma: Their Platelet Activating Factor (PAF) Antagonistic Activity and in Silico Insights into the PAF Receptor Binding Mode.

Three new tetrahydrobenzofuran-6(2 H)-one-type neolignans, heterochromins A-C (1-3), along with a bicyclo[3.2.1]octane neolignan, cinerin C (4), were isolated from an ethanol extract from the leaves of Ocotea heterochroma, a native plant growing in the Colombo-Ecuadorian region of the Andes. The chemical structures of 1-3 were elucidated by spectroscopic methods. The platelet activating factor (PAF) antagonistic activity was tested in vitro for these compounds. Additionally, their binding mode to the PAF receptor was studied by molecular docking and molecular dynamics simulations in order to rationalize such activity. Heterochromin A (1) was found to be a potent PAF antagonist with a favorable molecular profile for interacting with the PAF receptor binding site.

In vitro anti-atherogenic properties of traditional Greek cheese lipid fractions

Given that platelet activating factor (PAF) is a crucial inflammatory phospholipid mediator that is implicated in the mechanism of atherogenesis, the presence of PAF inhibitors in food reinforces their nutritional value in terms of protection against cardiovascular diseases. The aim of the present study was to evaluate the anti-atherogenic (anti-inflammatory) properties of two different types of Greek cheese: Kefalotyri and Ladotyri. Total lipids (TL) of both types of cheese samples were extracted by the method of Bligh and Dyer and separated into total polar lipids (TPL) and total neutral lipids (TNL) by countercurrent distribution. TPL were further separated by preparative thin-layer chromatography (TLC). TL, TPL, TNL and the obtained polar lipid fractions after TLC separation were tested to determine their biological activity towards atherosclerosis based on the in vitro inhibition of PAF-induced platelet aggregation. Both types of cheese samples exhibited strong biological activity, and their lipids were potent PAF inhibitors. Comparing the two types of cheese samples, Ladotyri cheese polar lipid fractions were found to exhibit stronger inhibitory properties than those of Kefalotyri cheese. The fact that both types of cheese were found to contain PAF inhibitors highlights their nutritional value in terms of cardio-protection.

The intestinal anti‐inflammatory effect of dersalazine sodium is related to a down‐regulation in IL‐17 production in experimental models of rodent colitis

Dersalazine sodium (DS) is a new chemical entity formed by combining, through an azo bond, a potent platelet activating factor (PAF) antagonist (UR-12715) with 5-aminosalicylic acid (5-ASA). DS has been demonstrated to have anti-inflammatory effects on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats and recently in UC patients in phase II PoC. There is Increasing evidence that Th17 cells have an important role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to further characterize the anti-inflammatory effects of DS. Effect of DS (10 or 30 mg·kg(-1) b.i.d.) on TNBS-induced colitis in rats was studied after 2 and 7 days with special focus on inflammatory mediators. Additionally, its anti-inflammatory properties were analysed in two different models of dextran sodium sulphate (DSS)-induced colitis, BALB/c and C57BL/6 mice, the latter being dependent on IL-17. DS, when administered for 7 days, showed intestinal anti-inflammatory effects in TNBS-induced colitis; these effects were observed both macroscopically and through the profile of inflammatory mediators (TNF, IL-1β, IL-6 and IL-17). Although the 2 day treatment with DS did not induce intestinal anti-inflammatory effects, it was sufficient to reduce the enhanced IL-17 expression. DS showed beneficial effects on DSS-induced colitis in C57BL/6 mice and reduced colonic pro-inflammatory cytokines IL-1β, IL-6 and IL-17. In contrast, it did not exert intestinal anti-inflammatory effects on DSS-induced colitis in BALB/c mice. DS exerts intestinal anti-inflammatory activity in different rodent models of colitis through down-regulation of IL-17 expression.

Inhibitory effects of phylligenin and quebrachitol isolated from Mitrephora vulpina on platelet activating factor receptor binding and platelet aggregation.

Phylligenine, together with quebrachitol, stigmasterol and two aporphine alkaloids—oxoputerine and liriodenine—were isolated from the twigs of Mitrephora vulpina C.E.C. Fisch. They were evaluated for their ability to inhibit platelet activating factor (PAF) receptor binding to rabbit platelets using 3H-PAF as a ligand and their antiplatelet aggregation effect in human whole blood induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Of all the compounds tested, phylligenin and quebrachitol exhibited potent and concentration-dependent inhibitory effects on PAF receptor binding, with IC50 values of 13.1 and 42.2 µM, respectively. The IC50 value of phylligenin was comparable to that of cedrol (10.2 µM), a potent PAF antagonist. Phylligenin also showed strong dose-dependent inhibitory activity on platelet aggregation induced by AA and ADP.

Vascular PAR-1: Activity and Antagonism

Despite major advances in antiplatelet therapies, recurrent cardiovascular events remain high after acute coronary syndrome. Furthermore, incremental benefits achieved in the reduction of atherothrombotic events have almost always been at the expense of hemorrhagic side effects. Thrombin is the most potent platelet activating factor known and it makes important interactions with the endothelium and vascular smooth muscle with proinflammatory, proatherogenic effects. Distinct from its activity within the coagulation cascade, thrombin mediates these effects via protease-activated receptor type 1 (PAR-1) in man. This review discusses the role of PAR-1 in the vasculature and the development of novel PAR-1 antagonists. These drugs may provide important antiatherothrombotic effects without attendant bleeding complications and could represent a major breakthrough for the treatment of cardiovascular diseases.

Futura study: evaluation of efficacy and safety of rupatadine fumarate in the treatment of persistent allergic rhinitis

Allergic rhinitis affects 10-30% of the population, negatively impacting one's quality of life and productivity. It has been associated with sinusitis, otitis media, sleep disorders, and asthma. Rupatadine is a second generation antihistamine with increased affinity to histamine receptor H1; it is also a potent PAF (platelet-activating factor) antagonist. It starts acting quite quickly, offers long lasting effect, and reduces the chronic effects of rhinitis.this study aims to assess the efficacy and safety of rupatadine in the treatment of persistent allergic rhinitis.this is a multi-centric open prospective study. This study included 241 patients from 13 centers in Brazil and was held between October of 2004 and August of 2005. Signs and symptoms of rhinitis and tolerance to medication were analyzed after one and two weeks of treatment.reduction on general scores from 8.65 to 3.21 on week 2 (p<0.001). All signs and symptoms improved significantly in the first day of treatment (p<0.001), except for nasal congestion and secretion, which improved from the second day of treatment (p<0.001). Adverse events occurred in 19.9% of the cases, 27.7% on week 1.rupatadine effectively controls persistent allergic rhinitis; it is safe and presents low incidence of side effects.

FUTURA STUDY-Evaluation of efficacy and safety of rupatadine fumarate in the treatment of persistent allergic rhinitis

SummaryAllergic rhinitis affects 10-30% of the population, negatively impacting one's quality of life and productivity. It has been associated with sinusitis, otitis media, sleep disorders, and asthma. Rupatadine is a second generation antihistamine with increased affinity to histamine receptor H1; it is also a potent PAF (platelet-activating factor) antagonist. It starts acting quite quickly, offers long lasting effect, and reduces the chronic effects of rhinitis.Aimthis study aims to assess the efficacy and safety of rupatadine in the treatment of persistent allergic rhinitis.Materials and methodthis is a multi-centric open prospective study. This study included 241 patients from 13 centers in Brazil and was held between October of 2004 and August of 2005. Signs and symptoms of rhinitis and tolerance to medication were analyzed after one and two weeks of treatment.Resultsreduction on general scores from 8.65 to 3.21 on week 2 (p<0.001). All signs and symptoms improved significantly in the first day of treatment (p<0.001), except for nasal congestion and secretion, which improved from the second day of treatment (p<0.001). Adverse events occurred in 19.9% of the cases, 27.7% on week 1.Conclusionrupatadine effectively controls persistent allergic rhinitis; it is safe and presents low incidence of side effects.

Macrophyllin-Type Bicyclo[3.2.1]octanoid Neolignans from the Leaves of Pleurothyrium cinereum

Four new macrophyllin-type bicyclo[3.2.1]octanoid neolignans, (7S,8R,3'S,5'R)-Delta(8')-5,5',3'-trimethoxy-3,4-methylenedioxy-2',3',4',5'-tetrahydro-2',4'-dioxo-7.3',8.5'-neolignan (cinerin A), 1, (7R,8R,3'S,4'R,5'R)-Delta(8')-4'-hydroxy-5,5'-dimethoxy-3,4-methylenedioxy-2',3',4',5'-tetrahydro-2'-oxo-7.3',8.5'-neolignan (cinerin B), 2, (7S,8R,3'R,4'S,5'R)-Delta(8')-4'-hydroxy-5,5',3'-trimethoxy-3,4-methylenedioxy-2',3',4',5'-tetrahydro-2'-oxo-7.3',8.5'-neolignan (cinerin C), 3, and (7S,8R,2'R,3'S,5'R)-Delta(8')-2'-hydroxy-5,5'-dimethoxy-3,4-methylenedioxy-2',3',4',5'-tetrahydro-4'-oxo-7.3',8.5'-neolignan (cinerin D), 4, along with the known diterpene kaurenoic acid 5, were isolated from the leaves of Pleurothyrium cinereum. The structures and configuration of these compounds were determined by extensive spectroscopic analysis. Cinerins A-D (1-4) were tested for their inhibition efficacy of platelet activating factor (PAF)-induced aggregation of rabbit platelets. Compound 3 was the most potent PAF antagonist. Compounds 1-5 were tested against Mycobacterium tuberculosis (H(37)Rv strain) using the MABA method. Compound 5 induced 91.3% growth inhibition at 50 microg mL(-1). Compounds 1-5 showed no significant inhibitory activity against some Gram-positive and Gram-negative bacteria by the agar-well diffusion method.

Involvement of endogenous leukotriene B4 and platelet‐activating factor in polymorphonuclear leucocyte recruitment to dermal inflammatory sites in rats

A critical role for leukotriene B(4) (LTB(4)) and/or platelet-activating factor (PAF) in regulating polymorphonuclear cell (PMN) trafficking to inflammatory sites has been reported in a number of experimental inflammatory models. In vitro, newly synthesized LTB(4) and PAF were shown to act in an autocrine/paracrine or intracrine fashion to enhance intracellular arachidonic acid availability and leukotriene biosynthesis. This suggested potentially cooperative effects of these lipid mediators in regulating PMN extravasation. The present study aimed to elucidate whether endogenous LTB(4) and PAF may both act to regulate plasma extravasation and PMN trafficking to inflammatory sites in experimental inflammation. With this aim, we have used selective and potent PAF and LTB(4) receptor antagonist pretreatments in dermal and pulmonary inflammation models in rats. Our results show additive inhibitory effects of dual LTB(4) and PAF receptor blockade in either PAF- or LTB(4)-elicited cutaneous PMN accumulation compared to single-drug administration. Furthermore, the combined administration of the drugs inhibited the PMN accumulation induced by the chemically unrelated soluble agonists tumour necrosis factor-alpha and C5a. Finally, in a model of pulmonary inflammation induced by the intravenous injection of Sephadex beads, lung neutrophilia was reduced by 63% following the administration of LTB(4) and PAF antagonists, in contrast with the lack of effect of single drug administration. Our results strongly support a role of both endogenous LTB(4) and PAF in regulating PMN trafficking to inflammatory sites in various experimental conditions.

Platelet-activating factor (PAF) receptor binding antagonists from Alpinia officinarum

The bioassay-guided purification of ether extracts of Alpinia officinarum led to the isolation of two new compounds 6-hydroxy-1,7-diphenyl-4-en-3-heptanone (1) and 6-(2-hydroxy-phenyl)-4-methoxy-2-pyrone (4) as well as three known compounds 1,7-diphenyl-4-en-3-heptanone (2), 1,7-diphenyl-5-methoxy-3-heptanone (3), and apigenin (5). Their structures were established on the basis of spectral methods. All three diarylheptanoids 1, 2, and 3 exhibited potent PAF receptor binding inhibitory activities with an IC(50) of 1.3, 5.0, and 1.6 microM, respectively. These studies have identified diarylheptanoids as a novel class of potent PAF antagonists.

Effects of Ginkgolide B on 6-OHDA-induced apoptosis and calcium over load in cultured PC12

Ginkgolide B, one of the major components of Ginkgo biloba extracts, is a potent platelet-activating factor (PAF) receptor antagonist, which is also regarded as having neuroprotective effects on the CNS. The aim of this research is to observe the effects of Ginkgolide B on the PC12 apoptosis induced by 6-hydroxydopamine (6-OHDA) and to explore whether these effects are related to the changes of intracellular Ca2+ and Calbindin D28K mRNA in PC12 cells. In the present work, the damage of PC12 cells was induced by 100μM 6-OHDA. The cells survival rate was examined by MTT assays. The intracellular free calcium concentration in PC12 cells was measured by using the fluorescent Ca2+ indicator fluo-3/AM. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was employed to determine the expression of Calbindin D28K mRNA in PC12. The data show that the Ginkgolide B inhibited PC12 cells apoptosis induced by 6-OHDA in a dose-dependent manner, and decreased the activity of caspase-3. In addition, Ginkgolide B increased the expression of Calbindin D28K mRNA and inhibited 6-OHDA-induced elevation in the intracellular calcium concentration. Our results showed that the Ginkgolide B inhibited the apoptosis of PC12 induced by 6-OHDA, and the protective effects of Ginkgolide B on PC12 cells are mediated, at least in part, by up-regulating the Calbindin D28K mRNA and by decreasing the intracellular calcium concentration.

Platelet-activating factor antagonist (ABT-491) decreases neuronal apoptosis in neonatal rat model of hypoxic ischemic brain injury

Hypoxic ischemic brain injury (HIBI) is a common cause of neonatal mortality and morbidity. To date, no study has investigated the role of platelet-activating factor (PAF) antagonists on neuronal apoptosis in neonatal rat model of HIBI. In the present study, we evaluated the effect of a highly potent and selective PAF antagonist (ABT-491) on neuronal apoptosis in neonatal rat model of HIBI. Seven-day-old Wistar rat pups were subjected to right common carotid artery ligation and hypoxia (92% nitrogen and 8% oxygen) for 2 h. They were treated with ABT-491 or saline either immediately before or after hypoxia. In sham group animals, neither ligation, nor hypoxia was performed. Neuronal apoptosis was evaluated by the terminal-transferase mediated dUTP biotin nick-end-labeling (TUNEL) and caspase-3 staining methods. Administration of ABT-491 either before or after hypoxia resulted in significant reduction of the numbers of apoptotic cells in both hemispheres, when compared to saline treatment group. The numbers of apoptotic cells in right hemispheres in all groups were significantly higher than that in the left hemispheres. These results suggested that ABT-491, a highly potent and selective PAF antagonist, administration either before or after hypoxia reduces apoptosis and we propose that ABT-491 may be a novel approach in the treatment of HIBI.

Amelioration of experimental acute pancreatitis with a potent platelet-activating factor antagonist.

The effect of a potent platelet-activating factor (PAF) antagonist, BB-882, on an experimental model of acute pancreatitis induced in male Wistar rats by a technique of microvascular ischaemia was studied. A single intraperitoneal injection of BB-882 (5 mg/kg) 30 min after induction of the disease in 12 animals significantly reduced (P < 0.001) the rise in the level of serum amylase (mean 2477 (range 2100-3280) units/l) compared with that in 12 control animals (mean 3928 (range 2800-5900) units/l) and significantly improved (P < 0.001) the mean pancreatic histology score (5.0 (range 3-10) versus 12.3 (range 8-18) in controls). PAF is a biologically active ether phosphorylcholine synthesized in cell membranes and a potent inflammatory mediator. Pancreatic tissue levels of this compound are increased in experimental acute pancreatitis and pretreatment with PAF receptor antagonists can ameliorate the progression of this disease. BB-882 alters the early course of experimental pancreatitis and may have a clinical therapeutic role.

Identification of Class 2 1-Deoxy-D-xylulose 5-Phosphate Synthase and 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase Genes fromGinkgo bilobaand Their Transcription in Embryo Culture with Respect to Ginkgolide Biosynthesis

Diterpenoid ginkgolides having potent platelet-activating factor antagonist activity are major active ingredients of ginkgo extract. Class 2-type 1-deoxy-D-xylulose 5-phosphate synthase (GbDXS2) and 1-deoxy-D-xylulose 5-phosphate reductoisomerase (GbDXR), the first two enzymes in 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, operating in the earlier step of ginkgolide biosynthesis, were cloned from embryonic roots of Ginkgo biloba through a homology-based polymerase chain reaction for role assessment of the enzymes. Plasmids harboring each gene rescued the respective knockout E. coli mutants. The levopimaradiene synthase gene (LPS), responsible for the first committed step in ginkgolide biosynthesis, and GbDXS2 were transcribed exclusively in embryonic root, suggesting a specific role of GbDXS2 in ginkgolide biosynthesis. GbDXR retained a higher transcription level in roots than in leaves, whereas class 1 DXS (GbDXS1) showed 30 to 50 % higher level in leaves. Ginkgolides and bilobalide were found both in leaves and roots from an earlier stage of the embryo culture. Exclusive transcription of ginkgolide biosynthesis-specific LPS and GbDXS2 in roots and the appearance of ginkgolides in leaves was consistent with translocation of the compounds from roots to leaves.

14-Deoxyandrographolide as a Platelet Activating Factor Antagonist in Bovine Neutrophils

14-Deoxyandrographolide (14-DAP) is a labdane diterpene isolated from Andrographis paniculata with previously reported calcium channel blocking activity. Its potential platelet activating factor (PAF) antagonistic activity in bovine neutrophils was assessed. 14-DAP, in concentrations between 10-100 microM, reduced the extracellular acidification rate and the intracellular alkalinization in a dose-dependent manner. In addition, 14-DAP reduced PAF-induced calcium flux in the presence of extracellular calcium, and tyrosine phosphorylation of a 44 kDa protein corresponding to the MAPK(ERK1). However, 14-DAP reduced the 3H-PAF binding with a Ki of 7.8 x 10 (- 9)M, and a Hill slope of 0.63, suggesting that there is more than one binding site for 14-DAP. We concluded that 14-DAP is an effective antagonist of PAF-mediated processes in bovine neutrophils, probably by virtue of its calcium channel blocking property.

Apafant, a Potent Platelet-Activating Factor Antagonist, Blocks Eosinophil Activation and Is Effective in the Chronic Phase of Experimental Allergic Conjunctivitis in Guinea Pigs

Platelet-activating factor (PAF) plays important roles in allergic reactions. In particular, there are many concerns about PAF, eosinophils, and the chronicity of allergic diseases. The purpose of the present studies is to elucidate the role of PAF in eosinophil activation at conjunctiva and to confirm the efficacy of Apafant (a potent PAF antagonist) ophthalmic solution in chronic experimental allergic conjunctivitis. Guinea pigs were actively immunized and allergic conjunctivitis was induced by repetitive instillation of 2.5% ovalbumin. PAF solution was topically applied and eosinophil activation was assessed by measuring the eosinophil peroxidase (EPO) activity in the tear fluid. Itch-scratching episodes and clinical symptoms scores were evaluated in the repetitive challenge conjunctivitis. From the instillation of PAF solution into guinea pig eyes, which were in a state of chronic allergic conjunctivitis, a significant increase in EPO activity was observed, and this increase was inhibited by pretreatment with Apafant. In the repetitive challenge model, the animals treated with Apafant ophthalmic solution showed a significant reduction of clinical symptoms and the itch-scratch response in both the first and the second challenges. PAF has an activity, that induces mediator release from eosinophils in the conjunctival tissues and may be involved in the chronic phase of allergic conjunctivitis.

Preparation of 7-substituted ginkgolide derivatives: potent platelet activating factor (PAF) receptor antagonists.

Ginkgolides are structurally unique constituents of Ginkgo biloba extracts and are known antagonists of the platelet-activating factor (PAF) receptor. Ginkgolide C is 25-fold less potent than ginkgolide B as a PAF receptor antagonist, due to the presence of the 7beta-OH. Recently, we found that 7alpha-fluoro ginkgolide B was equipotent to ginkgolide B underlining the critical importance of the 7-position of ginkgolides for PAF receptor activity. Herein we describe the synthesis of a series of ginkgolide B derivatives with modifications at the 7-position and the pharmacological evaluation of these derivatives as assayed by cloned PAF receptors. In two cases nucleophilic attack on a 7beta-O-triflate ginkgolide B did not lead to the expected products, but gave rise to two unprecedented ginkgolide derivatives, one with a novel rearranged skeleton. Furthermore, standard reduction of 7alpha-azido ginkgolide B did not give the expected primary amine, but instead yielded alkylated amines depending on the solvent employed. Pharmacological testing with cloned PAF receptors showed that ginkgolides with 7alpha-substitutents had increased affinity compared to 7beta-substituents, in particular 7alpha-chloro ginkgolide B, the most potent nonaromatic ginkgolide derivative described to date with a K(i) value of 110 nM.