Acyl-hydrazide derivatives of a xanthine carboxylic congener (XCC) as selective antagonists at human A2B adenosine receptors

Autor: Joel Linden, Xiao-duo Ji, Kenneth A. Jacobson, Yishai Karton, Yong-Chul Kim, Neli Melman
Rok vydání: 1999
Předmět:
Zdroj: Drug Development Research. 47:178-188
ISSN: 1098-2299
0272-4391
DOI: 10.1002/(sici)1098-2299(199908)47:4<178::aid-ddr4>3.0.co;2-l
Popis: The structure–activity relationships (SAR) of 8-phenyl-1,3-dipropylxanthine derivatives in binding to recombinant human A2B adenosine receptors were explored, in order to identify selective antagonists. Based on the finding of receptor selectivity in MRS 1204, containing an N-hydroxysuccinimide ester attached through the p-position of the 8-phenyl substituent [Jacobson et al. (1999): Drug Dev. Res., 47:45–53], a hydrazide and its more stable imide derivatives were synthesized. The hydrazide of XCC (8-[4-[[[carboxy]methyl]oxy]phenyl]-1,3-dipropylxanthine) was acylated with a variety of mono- and dicarboxylic acids. Ki values were determined in the adenosine receptor binding assays. At recombinant human A2B receptors expressed in membranes of HEK-293 cells, antagonist radioligands used were the xanthine 125I-ABOPX (125I-3-(4-amino-3-iodobenzyl)-8-oxyacetate-1-propyl-xanthine) and the nonxanthine antagonist [3H]ZM 241385 ([3H]4-(2-[7-amino-2-{furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-ylamino-ethyl)phenol). The initial screening utilized rat A1/A2A receptors and human A3 receptors, and selected compounds were examined at the human A1/A2A subtypes. A 1,2-dimethylmaleimide derivative, 14 (MRS 1595), bound to human A2B receptors with a Ki of 19 nM and proved to be selective vs. human A1/A2A/A3 receptors by 160-, and 35-fold, respectively. Enprofylline (3-propylxanthine) is slightly selective for A2B receptors, suggesting removal of the 1-propyl group; however, combination of the 1-H-3-Pr and 8-phenyl substituents eliminated the selectivity. Other potent and moderately selective A2B antagonists were a tetrahydrophthaloyl derivative 18b (MRS 1614, Ki value 10 nM) and amino acid conjugates of the XCC-hydrazide, i.e., the glutarimide 24b (MRS 1626, Ki value 13 nM), and protected dipeptide 27 (MRS 1615, Ki value 11 nM). Drug Dev. Res. 47:178–188, 1999. Published 1999 Wiley-Liss, Inc.
Databáze: OpenAIRE
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