A Novel A_1 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 Asth

摘要

Adenosine,an important signaling molecule in asthma,produces bronchoconstriction in asthmatics.Adenosine produces bronchoconstriction in allergic rabbits,primates,and humans by activating A_1 adenosine receptors(ARs).Effects of 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] a water-soluble,small molecule A_1AR 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.Hyper-responsiveness 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 PC_(30)was significantly higher(p < 0.05;n = 5)after L-97-1 at 24 h compared with histamine PC_(30)at 24 h after HDM.Adenosine PC_(30)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 A_1ARs 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.