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Derivatives of the Triazoloquinazoline Adenosine Antagonist (CGS15943) Are Selective for the Human A3 Receptor Subtype

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Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810
Cite this: J. Med. Chem. 1996, 39, 21, 4142–4148
Publication Date (Web):October 11, 1996
https://doi.org/10.1021/jm960482i
Copyright © 1996 American Chemical Society

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    Abstract

    The adenosine antagonist 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943) binds to human A3 receptors with high affinity (Ki = 14 nM), while it lacks affinity at rat A3 receptors. Acylated derivatives of the 5-amino group and other modifications were prepared in an effort to provide A3 subtype selectivity. Affinity was determined in radioligand binding assays at rat brain A1 and A2A receptors using [3H]-(R)-PIA ([3H]-(R)-N6-(phenylisopropyl)adenosine) and [3H]CGS 21680 ([3H]-2-[[4-(2-carboxy ethyl)phenyl]ethylamino]-5‘-(N-ethylcarbamoyl)adenosine), respectively. Affinity was determined at cloned human A3 receptors using [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)-5‘-(N-methylcarbamoyl)adenosine). A series of straight chain alkyl amides demonstrated that the optimal chain length occurs with the 5-N-propionyl derivative, 3, which had a Ki value of 7.7 nM at human A3 receptors, and was 40- and 14-fold selective vs rat A1 and A2A receptors, respectively. The 5-N-benzoyl derivative, 10, displayed Ki values of 680 and 273 nM at rat A1 and A2A receptors, respectively, and 3.0 nM at human A3 receptors. A 5-N-phenylacetyl derivative, 12, was 470-fold selective for human A3 vs rat A1 receptors with a Ki value of 0.65 nM. A conjugate of Boc-γ-aminobutyric acid was also prepared but was nonselective. Conversion of the 5-amino group of CGS15943 to an oxo function resulted in lower affinity but 15-fold selectivity for human A3 receptors.

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    *

     Correspondence to:  Dr. K. A. Jacobson, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel:  (301) 496-9024. Fax:  (301) 480-8422. E-mail:  [email protected].

     Abstract published in Advance ACS Abstracts, October 1, 1996.

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