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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 14, 2005; DOI: 10.1124/jpet.105.088179

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Peter C M Obiefuna
Ahmed Nadeem
Syed Jamal Mustafa
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Received for publication April 19, 2005.
Revised July 12, 2005.
Accepted for publication July 12, 2005.

A Novel A1 Adenosine Receptor Antagonist (L-97-1) Reduces Allergic Responses to House Dust Mite in an Allergic Rabbit Model of Asthma

Peter C M Obiefuna 1, V K Batra 2, Ahmed Nadeem 3, Paul Borron 2, Constance N Wilson 2, Syed Jamal Mustafa 1*

1 Department of Pharmacology, East Carolina University 2 Endacea Inc, Research Triangle Park, NC 3 East Carolina University

* Address correspondence to: E-mail: mustafas{at}mail.ecu.edu

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 (AR). Effects of L-97-1, 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 AU) extract within 24 h of their birth. Booster HDM injections were given weekly for one month, biweekly for 4 months and continued monthly thereafter. Hyper-responsivenessness was monitored by measuring lung dynamic compliance (Cdyn), following 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 (10mg/kg) solution or an equivalent volume of saline. Cdyn was significantly higher following treatment with L-97-1 compared to untreated controls (p<0.05, n=5). Histamine PC30 was significantly higher (p<0.05, n=5) following L-97-1 at 24 h compared to histamine PC30 at 24 h following HDM. Adenosine PC30 was significantly higher at 15 min and 6 h following L-97-1 compared to control (p<0.05, n=5). L-97-1 showed strong affinity for human A1 ARs in radioligand binding studies and no inhibition towards 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-responsive and HDM-induced EAR and LAR in rabbits by blocking A1 ARs and may be beneficial as an oral therapy for human asthma.


Key words: A1 adenosine receptor, Adenosine, L-97-1, allergen, asthma, hyper-responsiveness


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