Subject(s)
Academic Medical Centers , Facility Design and Construction/standards , Research Support as Topic/methods , Budgets , Electric Wiring , Facility Design and Construction/methods , Guidelines as Topic , Planning Techniques , Research Support as Topic/economics , Sanitary Engineering , United StatesABSTRACT
A series of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines with substitutions in the 2, 3, and 7 positions was prepared. The compounds were evaluated in the rat passive cutaneous anaphylaxis test for antiallergy activity. Several compounds had potent oral activity and were found to be superior to disodium cromoglycate and doxantrazole. Structure-activity relationships are discussed.
Subject(s)
Hypersensitivity/drug therapy , Pyrimidines/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Passive Cutaneous Anaphylaxis/drug effects , Pyrimidines/pharmacology , RatsSubject(s)
Asthma/drug therapy , Quinazolines/pharmacology , Animals , Cromolyn Sodium/administration & dosage , Passive Cutaneous Anaphylaxis/drug effects , Pyrazoles/administration & dosage , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Quinazolines/administration & dosage , Quinazolines/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
A series of 4-oxopyrano[3,2-b]indole carboxylic acids, tetrazoles, and carboxamidotetrazoles has been prepared and tested for antiallergy potential in the rat passive cutaneous anaphylaxis (PCA) assay. Many of the compounds showed activity comparable or superior to that of cromolyn sodium or doxantrazole. Several compounds were orally active.
Subject(s)
Indoles/chemical synthesis , Passive Cutaneous Anaphylaxis/drug effects , Pyrans/chemical synthesis , Pyrones/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Indoles/pharmacology , Pyrones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A series of substituted 10-oxo-10H-pyridazino[6,1-b]quinazoline-2-carboxylic acids was prepared and evaluated as antiallergy agents. The 8-chloro and unsubstituted analogues were more potent that cromolyn sodium and doxantrazole intravenously in the rat PCA test. None of the analogues possessed significant oral activity.
Subject(s)
Hypersensitivity/drug therapy , Quinazolines/chemical synthesis , Animals , Passive Cutaneous Anaphylaxis/drug effects , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Quinazolines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A series of substituted 11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acids were prepared and evaluated as antiallergy agents. Several analogues were orally active. 2-Methyl-11-oxo-11H-pyrido[2,1-b]quinoazoline-8-carboxylic acid (6) was superior to cromolyn sodium and doxantrazole orally and intravenously in the rat PCA test and a rat allergic bronchospasm model.
Subject(s)
Hypersensitivity/drug therapy , Quinazolines/chemical synthesis , Animals , Bronchial Spasm/drug therapy , Bronchial Spasm/immunology , Bronchial Spasm/physiopathology , Histamine Release/drug effects , In Vitro Techniques , Mast Cells/drug effects , Mast Cells/immunology , Passive Cutaneous Anaphylaxis/drug effects , Pulmonary Ventilation/drug effects , Quinazolines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A new series of 11-oxo-11H-pyrido[2,1-b]quinazolinecarboxylic acids and related analogues has been synthesized and evaluated as potential antiallergy agents. In the rat PCA test, 11-oxo-11H-pyrido[2,1--b]quinazoline-8-carboxylic acid is orally active and more potent than cromolyn sodium or doxantrazole intravenously.
Subject(s)
Passive Cutaneous Anaphylaxis/drug effects , Quinazolines/chemical synthesis , Animals , Guinea Pigs , Histamine Antagonists/chemical synthesis , In Vitro Techniques , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Quinazolines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
After administering 14C-labeled 3-(hydroxymethyl)-8-methoxychromone to rats by gavage, plasma was found to contain unchanged compound and three unconjugated metabolites. These metabolites were identified as 3-carboxy-8-methoxychromone, 8-methoxychromone, and 2-hydroxy-3-methoxyactophenone. The plasma levels of all four labeled compounds were determined from 30 min to 48 hr after drug administration. Only the levels of 3-(hydroxymethyl)-8-methoxychromone and 3-carboxy-8-methoxychromone correlated with the expression of antiallergy activity in the rat, and only these compounds were found to be active in vivo. However, a test system for the inhibition of anaphylactic histamine release in vitro showed activity only for 3-carboxy-8-methoxychromone.
Subject(s)
Chromones/metabolism , Animals , Dose-Response Relationship, Drug , Male , Mast Cells/metabolism , Passive Cutaneous Anaphylaxis/drug effects , Rats , Time FactorsABSTRACT
Previous studies had shown that cromolyn sodium would inhibit anaphylactic histamine release from rat peritoneal mast cells in vitro (J. Pharmacol. Exp. Ther. 184: 41, 1973), under conditions where the maximum release was usually less than 30% of the total. In this report, deuterium oxide (D2O) is shown to potentiate anaphylactic histamine release from rat peritoneal mast cells in vitro. The cells were sensitized in vitro with rat reaginic antiovalbumin and challenged in vitro. The histamine was measured fluorometrically. At 37 degrees C the effect of D2O was concentration dependent with a 1.3-fold potentiation at 5% (v/v) and a 3-fold potentiation at 25% D2O (v/v). There was no effect of these levels of D2O on spontaneous histamine release. To be able to measure the rate of release, the sensitized cells were challenged with antigen at 25 degrees C in the presence and absence of D2O. Under these conditions, D2O increased both the rate of release and the total amount of release proportionately so that the T1/2 of release was not affected by D2O. The concentration of cromolyn sodium necessary to obtain 50% inhibition of histamine release increased from 6 muM in 0% D2O, to 80 muM in 10% D2O and to greater than 500 muM in 25% D2O. However, the lines showing the relationship between cromolyn sodium concentration and percent histamine released were not shifted in a parallel manner by D2O. This suggests that the interaction between D2O, cromolyn sodium and the histamine-releasing processes of mast cells is not a simple one.
