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o-Aminoacetophenone is a pheromone produced by virgin honeybee queens and released with feces. In small social groups, the pheromone repels and is used to terminate agonistic interactions between queens and workers.
A one-step synthesis of hexahydrocannabinoid analogs (HHC) is described making use of the condensation of phenolic ketones and aldehydes with citronellal in the presence of pyridine.
Exposure of human basophils to purified phospholipase A2 caused a release of histamine, the process could be divided in one Ca2+-independent and one Ca2+-dependent stage. Low concentrations of mepacrine and p-bromophenacyl bromide (BPB) inhibited both phospholipase A2- and anti-IgE-induced histamine release. Mepacrine was more potent than BPB when the two-stage-method was used. The inhibition of mepacrine was most effective when the drug was added in the second Ca2+-dependent stage. The effect of mepacrine in the whole reaction of the anti-IgE-induced histamine release was biphasic and mepacrine was less effective than in the inhibition of the separated stages. The effect of BPB on the whole reaction was rather similar to mepacrine, although it was not biphasic. The results presented in this work confirm a previous hypothesis suggesting that activation of phospholipase A2 is an important step in the IgE-mediated histamine release process. The results also suggest that inhibition of histamine release due to inhibition of phospholipase A2 might be of therapeutical value as the system can be inhibited at very low drug concentrations.
The effect of the leukotriene antagonist, Ly 171,883, or the 5-lipoxygenase inhibitor, REV 5901, on ethanol-induced gastric lesion formation in the rat was investigated. Pretreatment with REV 5901 resulted in a dose dependent decrease in lesion length. Doses of 32 and 64 mg/kg induced nearly complete protection against ethanol, while doses of 1 and 8 mg/kg were much less effective. With Ly 171,883, 32 and 64 mg/kg doses less dramatically reduced lesion length. These findings implicate products of the 5-lipoxygenase pathway in the production of ethanol-induced gastric lesions.
Recent work from this laboratory has shown that macrophages in culture synthesize and secrete a soluble factor(s) that induces the synthesis of collagenase in primary cultures of rabbit chondrocytes (Arth. Rheum. 23, 448, 1980). The current studies were undertaken to determine the role of arachidonate metabolism in this process. Incubation of chondrocytes with MCM (Macrophage Conditioned Medium) and low doses of indomethacin (1-10 microM) had no effect on collagenase synthesis. The lipoxygenase inhibitor NDGA, indomethacin at high doses (50 microM), diethylcarbamazine and the phospholipase inhibitor dibromoacetophenone, inhibited the MCM dependent synthesis of collagenase in chondrocytes. These inhibitors did not affect collagenase activity nor did they interfere with the activation of latent collagenase. Our data indicate that although cyclooxygenase plays no role in the MCM dependent induction of collagenase in chondrocytes, lipoxygenase activity may be essential.
The effect of para-bromophenacyl bromide (a selective inhibitor of phospholipase A2) and pertussis toxin has been investigated on IgE-dependent histamine release and on IgE-dependent macrophage-mediated cytotoxicity. Para-bromophenacyl bromide inhibited dose-dependently IgE-dependent stimulation of mast cells and macrophages (IC50's of 5.0 X 10(-7) M and 2.5 X 10(-7) M, respectively). In contrast, pertussis toxin only inhibited the IgE-dependent stimulation of macrophages, whereas the IgE-dependent activation of mast cells was not affected. These results suggest that the transducing mechanisms following the activation of the high affinity receptor for IgE (Fc epsilon RI on mast cells) as well as the low affinity receptor for IgE (Fc epsilon RII on macrophages) induce the activation of phospholipase A2. Fc epsilon RII might be coupled to a pertussis toxin sensitive G-protein.
LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl] ethanone, is an orally active antagonist of LTD4- and LTE4-induced responses in a variety of test systems. We prepared a new series of LT antagonists based on a proposed model of LY171883 binding to the LTE4 receptor in which the n-propyl and tetrazole moieties of LY171883 occupy those parts of the receptor to which the C1-C5 chain and the cysteinyl carboxyl of LTE4 bind, respectively. The new compounds have an acidic function corresponding to the glycine carboxyl of LTD4 linked through a heterocyclic group which is proposed to bind to the LTD4 receptor where the cysteinyl glycine amide bond of LTD4 binds. LY203647, 1-[2-hydroxy-3-propyl-4-[4-[2-[4-(1H-tetrazol-5-yl)butyl]-2H- tetrazol-5-yl]butoxy]phenyl] ethanone, showed good LTD4 antagonist activity with a suitable pharmacologic and toxicologic profile and has been chosen for clinical evaluation.
PAF-acether (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) is released from several cell sources simultaneously with an inactive non-acylated compound (1-O-alkyl-glyceryl-3-phosphorylcholine) (lyso-PAF-acether). Formation of the latter probably results from the activation of a phospholipase A2 (PLA2). Indeed, the PLA2 inhibitors, bromophenacyl bromide (BPB), mepacrine, 874CB (100 microM), and EDTA (5 mM), blocked the zymosan-induced release of PAF-acether from PC. EDTA and BPB also markedly reduced the release of lyso-PAF-acether. To verify this hypothesis, acetyl coenzyme A (acetyl-CoA) was added to stimulated PC. This enhanced the release of PAF-acether in a dose-dependent fashion from 1 microM acetyl-CoA to reach a maximal increase - 200% - at 100 microM. Furthermore, using 3H acetyl-CoA, incorporation of labelled acetate into PAF-acether was suggested by (1) identical chromatographic patterns of biological activity and radioactivity; (2) disappearance of these activities after treatment with PLA2, but not after exposure to lipase from Rhizopus arrhizus. PAF-acether was also obtained when both acetyl-CoA (100 microM) and synthetic lyso-PAF-acether (0.2 microM) were added to unstimulated PC previously treated with BPB (100 microM for 10 min). These results suggest that the release of PAF-acether is the consequence of at least two different steps: (1) hydrolysis of 1-O-alkyl-2-acyl-glyceryl phosphorylcholine by PLA2; (2) enzymatic acetylation of the hydrolysis product.
We evaluated the inhibitory effect of DS-4574, a peptidoleukotriene antagonist with mast cell stabilizing action, on rat gastric mucosal lesions induced by compound 48/80 (C48/80: a mast cell degranulator), in comparison with those of disodium cromoglycate (DSCG: a mast cell stabilizer), LY171883 (a peptidoleukotriene antagonist) and cimetidine (a histamine H2 receptor antagonist). Subcutaneous administration of C48/80 (1 mg/kg) once daily for four consecutive days produced extensive gastric lesions in the fundic mucosa. DS-4574 (20, 50 and 100 mg/kg/day, oral) and DSCG (200 mg/kg/day, intraperitoneal) treatment markedly inhibited formation of these mucosal lesions, but LY171883 (100 and 200 mg/kg/day, oral) and cimetidine (400 mg/kg/day, oral) treatment did not. Moreover, DS-4574 and DSCG significantly suppressed both hyperhistaminemia and histamine release from rat peritoneal mast cells induced by C48/80. These results indicate that the inhibitory effect of DS-4574 on gastric lesions induced by C48/80 may be related to its mast cell stabilizing action, but to neither its antisecretory nor its peptidoleukotriene antagonistic activity.
The three types (groups I, II and III) of stable extracellular 14 kDa phospholipase A2 enzymes differ in their primary amino acid sequences and their properties. It may thus be possible to design low-molecular weight inhibitors targeted to the secretory form of mammalian PLA2. This enzyme has been implicated in inflammatory disorders. We have studied the inhibition of four distinct PLA2 enzymes by a range of NSAIDs, using 3H-oleate release from prelabelled membranes of E. coli for assay. The enzymes used were cobra venom PLA2 (Naja naja, a group I enzyme), bee venom PLA2 (Apis mellifera, group III), recombinant human synovial PLA2 (group II) and rat peritoneal PLA2 (group II). Under the conditions of the 3H-oleate E. coli assay, 1 mM concentrations of aspirin, sodium salicylate, paracetamol (acetaminophen), oxphenbutazone, ibuprofen, flurbiprofen and nabumetone failed to inhibit significantly any of the four enzymes. However, indomethacin inhibited all four enzymes, although effects were greatest on the two group II enzymes (rat peritoneal and human synovial PLA2). Approximate IC50 values were 28 and 35 microM, respectively. Inhibition by indomethacin was not time dependent and was greater at micromolar rather than millimolar levels of calcium. We conclude that indomethacin but not the other tested classes of NSAID inhibits the group II PLA2 enzyme in a selective manner and suggest that this may be relevant both to its clinical spectrum and to the design of novel pharmaceutical leads.
At concentrations of 3.75 micrograms/ml and greater the non-steroidal anti-inflammatory drugs, benoxaprofen and to a lesser extent flunoxaprofen, caused dose-related spontaneous activation of both luminol- and lucigenin-enhanced chemiluminescence in human polymorphonuclear leucocytes (PMNL) in vitro. Flunoxaprofen- and benoxaprofen-mediated activation of oxidant release by PMNL was increased by UV-radiation. Pre-incubation of PMNL with sub-stimulatory concentrations of both drugs greatly enhanced the release of reactive oxygen species on subsequent exposure of the cells to various standard stimuli of membrane-associated oxidative metabolism. The protein kinase C inhibitor, H-7, and the phospholipase A2 inhibitor, BPB, both prevented drug-mediated activation of superoxide generation by PMNL. Flunoxaprofen-mediated stimulation of PMNL membrane-associated oxidative metabolism is, like benoxaprofen, due to apparent activation of protein kinase C. These findings establish the pro-oxidative properties of flunoxaprofen.
At 10 min, 2 h and 4 h after induction of a reverse passive Arthus reaction (RPAR) in the pleural cavity of rats, pleural exudate was collected and analyzed in vitro for phospholipase A2 (PLA2) acyl hydrolytic activity. Inasmuch as exudate PLA2 was inhibited by addition of EDTA, the acyl hydrolytic activity appeared calcium-dependent. However, addition of exogenous calcium to the exudate had only a minor effect on the activity. Maximum hydrolysis in all exudates was observed over a pH range of 6-9 with a neutral optimum. The 4 h exudate PLA2 activity was almost fully inhibited by para-bromophenacyl bromide (pBPB), whereas the acyl hydrolytic activity in the 10 min and 2 h exudates was reduced by 44% and 46%, respectively, by 200 microM pBPB. Although the PLA2 in the 4 h exudate displayed an increased sensitivity to high exogenous calcium concentrations and to pBPB inactivation, the basic properties of the exudate PLA2 at the three time points appeared similar.
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Solutions of various concentrations of chloracetophenone (dissolved in 1, 1, 1, trichlorethane) were trickled on the corneas of rabbits. The substance was either applied to the center or to the limbus, or simultaneously to the center and limbus of the cornea. After surgical removal of the cornea on day 21, the alterations were examined by a light microscope. When chloractephenone was applied to the middle of the cornea, signs of intensified epithelial regeneration were observed, even to the point of a severe granulating and necrotic infection with ulceration. The severity of these changes depended on the concentration used and showed that repair of a corneal defect had been attempted. The same changes were observed when the same concentrations of chloracetophenone were applied to the limbus, but with greater severity. Some of these alterations led to perforation of the cornea when the substance was applied to center and limbus. These results are discussed in reference to the correlation of the changes seen in animal tests to those in the human eye.
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A new model of active anaphylactic reaction in mice was developed. The edematogenic reaction appeared 5 min after the intraplantar injection of ovalbumin, peaked at 30 min after the antigenic challenge, and decreased thereafter. Using the non-steroidal, anti-inflammatory agents indomethacin and aspirin, we found that cyclooxygenase products do not participate in the reaction. In contrast, vasoactive amines appear to be involved, because meclizine and methysergide reduced the edema. Dexamethasone, BW755C, LY 171883 and WEB 2170 effectively interfered with the edematogenic reaction, which suggests that lipid mediators such as leukotrienes and PAF play a role in the active anaphylactic response.