guanosine-5--o-(3-thiotriphosphate) and Bronchial-Hyperreactivity

Topics: Airway Resistance; Animals; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Count; CHO Cells; Cricetinae; Cricetulus; Guanosine 5'-O-(3-Thiotriphosphate); Histamine Agonists; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Serotonin

CC chemokine receptor 4 (CCR4) is generally recognized as a preferential marker for T helper 2 cells, and we have previously reported morpholine-derivative CCR4 antagonists, RS-1154 and RS-1269. Here, we investigate the pharmacological profiles of a novel pyrimidine-derivative CCR4 antagonist, 2-{4-[2-(diethylamino)ethoxy]phenyl}-N-(2,4-difluorobenzyl)-5-fluoropyrimidin-4-amine (RS-1748), which showed potency to inhibit the bindings of [(125)I]CCL17 and [(35)S]GTPgammaS to human CCR4-expressing Chinese hamster ovary (CHO) cells with IC(50) values of 59.9 nM and 18.4 nM, respectively. Furthermore, RS-1748 inhibited ovalbumin-induced airway inflammation in guinea pigs at a dose of 10 mg/kg. These results indicate that RS-1748 would be a promising lead compound for developing a therapeutic agent against asthma.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Chemokine CCL17; CHO Cells; Cricetinae; Cricetulus; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Humans; Inflammation; Inhibitory Concentration 50; Male; Ovalbumin; Pyrimidines; Receptors, CCR4

The antagonist and agonist binding sites of muscarinic receptors were investigated by using membrane preparations of airways from nonsensitized normal control, sensitized control and repeatedly antigen challenged rats. The in vitro bronchial responsiveness to ACh was markedly increased in repeatedly antigen challenged group but not in sensitized control group. No significant difference was observed in receptor density and antagonist affinity among these three groups. The affinity of ACh for high-affinity agonist binding sites of repeatedly antigen challenged group was much greater than those in the other groups; the affinity significantly reduced in the presence of GTP gamma S. We concluded that enhanced G protein level might be involved in inducing airway hyperresponsiveness in rats.

Topics: Acetylcholine; Animals; Antigens; Binding Sites; Bronchial Hyperreactivity; Computer Simulation; Dose-Response Relationship, Drug; Guanosine 5'-O-(3-Thiotriphosphate); Male; Muscarinic Agonists; Muscarinic Antagonists; Rats; Rats, Wistar; Receptors, Muscarinic