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

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

V. K. Batra (Creator)

P. Borron (Creator)

S. Jamal Mustafa (Creator)

A. Nadeem (Creator)

P. C. M. Obiefuna (Creator)

C. N. Wilson (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

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-hydroxy-ethyl)-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. 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 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 HDMinduced EAR and LAR in allergic rabbits by blocking A1 ARs and may be beneficial as an oral therapy for human asthma. Originally published Journal of Pharmacology and Experimental Therapies Vol. 315 No. 1 Oct 2005

Additional Information

Publication

Other

Journal of Pharmacology and Experimental Therapeutics. 315:1(October 2005) p. 329-336.

Language: English

Date: 2011

Keywords

adenosine, Asthma, L-97-1

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