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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

P. C. M. Obiefuna, V. K. Batra, A. Nadeem, P. Borron, C. N. Wilson and S. Jamal Mustafa
Journal of Pharmacology and Experimental Therapeutics October 2005, 315 (1) 329-336; DOI: https://doi.org/10.1124/jpet.105.088179
P. C. M. Obiefuna
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V. K. Batra
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A. Nadeem
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P. Borron
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C. N. Wilson
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S. Jamal Mustafa
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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.

Footnotes

  • This study was supported by North Carolina Biotechnology Center Kenan Award Collaborative Funding Assistance 2000 Collaborative Funding Grant 8002 and Small Business Technology Transfer Phase I Grant HL070458.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.105.088179.

  • ABBREVIATIONS: AR, adenosine receptor; 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; HDM, house dust mite; EAR, early allergic response; LAR, late allergic response; AU, allergen unit; Cdyn, dynamic compliance; BHR, bronchial hyper-responsiveness; 2-CADO, 2-chloroadenosine; PAEC, pulmonary artery endothelial cell; NMDA, N-methyl-d-aspartate; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; CGS 21680, 2-[p-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamidoadenosine; ANOVA, analysis of variance; MANOVA, multiple analysis of variance; PDE, phosphodiesterase; ASM, airway smooth muscle.

  • ↵1 Current address: Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV.

    • Received April 19, 2005.
    • Accepted July 12, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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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
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

P. C. M. Obiefuna, V. K. Batra, A. Nadeem, P. Borron, C. N. Wilson and S. Jamal Mustafa
Journal of Pharmacology and Experimental Therapeutics October 1, 2005, 315 (1) 329-336; DOI: https://doi.org/10.1124/jpet.105.088179

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

P. C. M. Obiefuna, V. K. Batra, A. Nadeem, P. Borron, C. N. Wilson and S. Jamal Mustafa
Journal of Pharmacology and Experimental Therapeutics October 1, 2005, 315 (1) 329-336; DOI: https://doi.org/10.1124/jpet.105.088179
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