title: A novel A1 adenosine receptor antagonist, L-97-1 [3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxy-ethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione], reduces allergic responses to house dust mite in an allergic rabbit model of asthma.
abstract: Adenosine, an important signaling molecule in asthma, produces bronchoconstriction in asthmatics. Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating A1 adenosine receptors (ARs). Effects of L-97-1 [3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxyethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione] a water-soluble, small molecule A1 AR antagonist were investigated on early and late phase allergic responses (EAR and LAR) in a hyper-responsive rabbit model of asthma. Rabbits were made allergic by intraperitoneal injections of house dust mite [HDM; 312 allergen units (AU)] extract within 24 h of their birth. Booster HDM injections were given weekly for 1 month, biweekly for 4 months, and continued monthly thereafter. Hyperresponsiveness was monitored by measuring lung dynamic compliance (Cdyn), after histamine or adenosine aerosol challenge in allergic rabbits. Hyper-responsive rabbits were subjected to aerosol of HDM (2500 AU), 1 h after intragastric administration of L-97-1 (10 mg/kg) solution or an equivalent volume of saline. Cdyn was significantly higher after treatment with L-97-1 compared with untreated controls (p < 0.05 n = 5). Histamine PC30 was significantly higher (p < 0.05; n = 5) after L-97-1 at 24 h compared with histamine PC30 at 24 h after HDM. Adenosine PC30 was significantly higher at 15 min and 6 h after L-97-1 compared with control (p < 0.05; n = 5). L-97-1 showed strong affinity for human A1 ARs in radioligand binding studies and no inhibition toward human phosphodiesterase II, III, IV, and V enzymes. These data suggest that L-97-1 produces a significant reduction of histamine or adenosine-induced hyper-responsiveness and HDM-induced EAR and LAR in allergic rabbits by blocking A1 ARs and may be beneficial as an oral therapy for human asthma.
authors: Department of Pharmacology, East Carolina University, Greenville, North Carolina, USA.
authors: P C M
authors: PC
authors: Obiefuna
authors: V K
authors: VK
authors: Batra
authors: A
authors: A
authors: Nadeem
authors: P
authors: P
authors: Borron
authors: C N
authors: CN
authors: Wilson
authors: S Jamal
authors: SJ
authors: Mustafa
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy*; D016535:Bronchial Hyperreactivity / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004391:Dust; D006632:Histamine / Q000494:pharmacology; D008925:Mites / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D043682:Receptor, Adenosine A1 / Q000032:analysis
chemical_list: C505457:3-(2-(4-aminophenyl)ethyl)-8-benzyl-7-(2-ethyl(2-hydroxyethyl)aminoethyl)-1-propyl-3,7-dihydropurine-2,6-dione; D058916:Adenosine A1 Receptor Antagonists; D018927:Anti-Asthmatic Agents; D004391:Dust; D010726:Phosphodiesterase Inhibitors; D011687:Purines; D043682:Receptor, Adenosine A1; D006632:Histamine; D000241:Adenosine