ABSTRACT
The transactivator of transcription, Tat, of human immunodeficiency virus type 1 (HIV-1) is required for viral replication. Inhibition of Tat function could have the potential to keep integrated provirus in dormancy. In the presence of Tat, Ro 24-7429, an analog of Ro 5-3335, inhibited expression of indicator genes controlled by the HIV-1 long terminal repeat promoter in transient transfection assays and in a constitutive cell line at noncytotoxic concentrations. Reduction of steady-state mRNA of the indicator gene by the compound correlated with reduction of the gene product in the constitutive cell line. Ro 24-7429 has broad activity against several strains of HIV-1 in different cell lines, peripheral blood lymphocytes, and macrophages (IC90 = 1-3 microM). Importantly, Ro 24-7429 inhibited viral replication in both acute and chronic infection in vitro, a characteristic expected of a Tat antagonist and not shared by viral reverse transcriptase inhibitors. Consistent with this, the compound reduced cell-associated viral RNA and proteins and partially restored cell-surface CD4 in chronically infected cells. After 2 years of continued weekly passage of the virus in fresh CEM cells grown in the presence of the compound at 1 or 10 microM, the virus did not develop resistance to the drug. These results indicate that the compound's action might involve a cellular factor.
Subject(s)
Antiviral Agents/pharmacology , Benzodiazepines , Gene Products, tat/antagonists & inhibitors , HIV-1/drug effects , Pyrroles , Alkaline Phosphatase/genetics , Animals , CD4 Antigens/biosynthesis , Cells, Cultured , Down-Regulation , Drug Evaluation, Preclinical , Drug Resistance, Microbial , HIV Long Terminal Repeat/genetics , Humans , Lymphocytes/microbiology , Macrophages/microbiology , Promoter Regions, Genetic/genetics , Serial Passage , Transcription, Genetic , Transfection , Up-Regulation , Virus Replication/drug effects , tat Gene Products, Human Immunodeficiency VirusABSTRACT
A series of 5H-pyrimido[5,4-d][2]benzazepines has been synthesized, starting from the corresponding 2-benzazepin-5-ones, and evaluated as potential anxiolytic agents. Selected compounds from this series show a pharmacological profile of action different than that of diazepam. They are more potent than diazepam in the anti-pentylenetetrazole test and in the [3H]diazepam binding assay, yet show less activity in the inclined screen test. A pharmacological data profile is given for 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (7c). The structure-activity relationships of these potential anxiolytic agents are discussed.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Benzazepines/chemical synthesis , Animals , Benzazepines/pharmacology , Biological Assay , Diazepam/metabolism , Drug Evaluation, Preclinical , Drug Interactions , Ethanol/pharmacology , Indicators and Reagents , Magnetic Resonance Spectroscopy , Male , Mice , Motor Activity/drug effects , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, Cell Surface/drug effects , Receptors, Cell Surface/metabolism , Receptors, GABA-A , Reflex/drug effects , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
The syntheses of some 1,4-benzodiazepines potentially useful as haptens are reported. These compounds are related to chlordiazepoxide, diazepam, nitrazepam, clonazepam, and some of their metabolites. The chemistry reported here is intended to support specific immunoassay development for these drugs.
Subject(s)
Benzodiazepines/immunology , Haptens/chemical synthesis , Benzodiazepines/analysis , Benzodiazepines/chemical synthesis , Chemical Phenomena , Chemistry , RadioimmunoassayABSTRACT
A number of analogues and derivatives of the title compound were synthesized and evaluated in a new test procedure used to detect topical antiinflammatory activity. Some general comments regarding observation on the structure-activity relationship of these compounds are made.
