ABSTRACT
Selective bradykinin (BK) B 1 receptor antagonists could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure activity relationships of the structurally novel HTS lead compound 1 provided potent hBK B 1 receptor antagonists with excellent receptor occupancy in the CNS of hBK B 1 transgenic rats.
Subject(s)
Amines/chemistry , Benzophenones/chemistry , Benzophenones/pharmacology , Bradykinin B1 Receptor Antagonists , Animals , Benzophenones/chemical synthesis , Cell Line , Dogs , Humans , Molecular Structure , Rats , Receptor, Bradykinin B1/metabolism , Structure-Activity RelationshipABSTRACT
Selective bradykinin (BK) B(1) receptor antagonists have been shown to be antinociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure-activity relationships of the biphenyl moiety of the lead compound 1 provided a potent new structural class of BK B(1) receptor antagonists.
Subject(s)
Analgesics/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Bradykinin B1 Receptor Antagonists , Cyclohexanes/chemistry , Hydrocarbons, Fluorinated/chemistry , Pyridines/chemistry , Analgesics/chemical synthesis , Analgesics/pharmacology , Animals , Animals, Genetically Modified , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclohexanes/chemical synthesis , Cyclohexanes/pharmacology , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Receptor, Bradykinin B1/genetics , Structure-Activity RelationshipABSTRACT
We have developed an efficient and selective radioligand, the [35S]-radiolabeled dihydroquinoxalinone derivative, 4, for an ex vivo receptor occupancy assay in transgenic rats over-expressing the human bradykinin B1 receptor.
Subject(s)
Bradykinin B1 Receptor Antagonists , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Animals , Animals, Genetically Modified , Binding, Competitive/drug effects , Humans , Isotope Labeling , Ligands , Radioligand Assay , Rats , Receptor, Bradykinin B1/chemistry , Structure-Activity Relationship , Sulfur RadioisotopesABSTRACT
Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity. The optimization of a screening lead compound, facilitated by a homology model of the BK B1 receptor, culminated in the discovery of a potent human BK B1 receptor antagonist. Results from site-directed mutagenesis studies and experiments in an animal pain model are presented.