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

• Published in: Drug development research Vol. 47; no. 4; pp. 178 - 188
• Main Authors: Kim, Yong-Chul, Karton, Yishai, Ji, Xiao-duo, Melman, Neli, Linden, Joel, Jacobson, Kenneth A.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.08.1999; Wiley-Liss
• Subjects: adenylyl cyclase; alkylxanthines; Biological and medical sciences; G protein-coupled receptors; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; purines; radioligand; structure-activity relationships; Human; Transfection; Structure activity relation; Established cell line; Molecular interaction; Acyl; Antagonist; Hydrazides; Xanthine; Chemical synthesis; In vitro; A2 Adenosine receptor
• ISSN: 0272-4391; 1098-2299; 1098-2299
• DOI: 10.1002/(SICI)1098-2299(199908)47:4<178::AID-DDR4>3.0.CO;2-L

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.