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N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors.
Bioorg Med Chem. 2007 Jul 15; 15(14):5003-17.BM

Abstract

Synthesis and physicochemical properties of N-benzyl pyrimido[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-chloropropylo-8-bromo-1,3-dimethyl- or 1,3-dipropyl xanthine derivatives with corresponding (un)substituted benzylamines. Dipropyl derivatives were obtained under microwave irradiation conditions either. The obtained compounds (1-20) were evaluated for their affinity to adenosine A1 and A2A receptors, selected compounds were additionally investigated for affinity to the A3 receptor subtype. The results of the radioligand binding assays to A1 and A2A adenosine receptors showed that most of the 1,3-dimethyl-9-benzylpyrimidopurinediones exhibited selective affinity to A2A receptors at micromolar or submicromolar concentrations (for example, derivative 9 with o-methoxy substituent displayed a Ki value of 0.699 microM at rat A2A receptor with more than 36-fold selectivity). Contrary to previously described arylpyrimido[2,1-f]purinediones dipropyl derivatives (compounds 15-20) showed affinity to both kinds of receptors increased, however A1 affinity increased to a larger extent, with the result that A2A selectivity was abolished. The best adenosine A1 receptor ligand was m-chlorobenzyl derivative 18 (Ki=0.089 microM and 5-fold A1 selectivity). Structure-activity relationships were discussed with the analysis of lipophilic and spatial properties of the investigated compounds. Pharmacophore model of adenosine A1 receptor antagonist was adopted for this purpose.

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Authors+Show Affiliations

Drabczyńska A
Jagiellonian University, Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, Pl 30-688 Kraków, Poland.
Müller CE
No affiliation info available
Karolak-Wojciechowska J
No affiliation info available
Schumacher B
No affiliation info available
Schiedel A
No affiliation info available
Yuzlenko O
No affiliation info available
Kieć-Kononowicz K
No affiliation info available

MeSH

AnimalsBenzeneCHO CellsChemical PhenomenaChemistry, PhysicalCricetinaeCricetulusCrystallography, X-RayHydrogen BondingMagnetic Resonance SpectroscopyMethylationModels, MolecularMolecular StructurePropanePurinesPyrimidinesRatsReceptor, Adenosine A1Receptors, Adenosine A2Structure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17499511

Citation

Drabczyńska, Anna, et al. "N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: Synthesis and Structure-activity Relationships at Adenosine A1 and A2A Receptors." Bioorganic & Medicinal Chemistry, vol. 15, no. 14, 2007, pp. 5003-17.
Drabczyńska A, Müller CE, Karolak-Wojciechowska J, et al. N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors. Bioorg Med Chem. 2007;15(14):5003-17.
Drabczyńska, A., Müller, C. E., Karolak-Wojciechowska, J., Schumacher, B., Schiedel, A., Yuzlenko, O., & Kieć-Kononowicz, K. (2007). N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors. Bioorganic & Medicinal Chemistry, 15(14), 5003-17.
Drabczyńska A, et al. N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: Synthesis and Structure-activity Relationships at Adenosine A1 and A2A Receptors. Bioorg Med Chem. 2007 Jul 15;15(14):5003-17. PubMed PMID: 17499511.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors. AU - Drabczyńska,Anna, AU - Müller,Christa E, AU - Karolak-Wojciechowska,Janina, AU - Schumacher,Britta, AU - Schiedel,Anke, AU - Yuzlenko,Olga, AU - Kieć-Kononowicz,Katarzyna, Y1 - 2007/04/19/ PY - 2006/07/14/received PY - 2007/03/30/revised PY - 2007/04/13/accepted PY - 2007/5/15/pubmed PY - 2007/8/9/medline PY - 2007/5/15/entrez SP - 5003 EP - 17 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 15 IS - 14 N2 - Synthesis and physicochemical properties of N-benzyl pyrimido[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-chloropropylo-8-bromo-1,3-dimethyl- or 1,3-dipropyl xanthine derivatives with corresponding (un)substituted benzylamines. Dipropyl derivatives were obtained under microwave irradiation conditions either. The obtained compounds (1-20) were evaluated for their affinity to adenosine A1 and A2A receptors, selected compounds were additionally investigated for affinity to the A3 receptor subtype. The results of the radioligand binding assays to A1 and A2A adenosine receptors showed that most of the 1,3-dimethyl-9-benzylpyrimidopurinediones exhibited selective affinity to A2A receptors at micromolar or submicromolar concentrations (for example, derivative 9 with o-methoxy substituent displayed a Ki value of 0.699 microM at rat A2A receptor with more than 36-fold selectivity). Contrary to previously described arylpyrimido[2,1-f]purinediones dipropyl derivatives (compounds 15-20) showed affinity to both kinds of receptors increased, however A1 affinity increased to a larger extent, with the result that A2A selectivity was abolished. The best adenosine A1 receptor ligand was m-chlorobenzyl derivative 18 (Ki=0.089 microM and 5-fold A1 selectivity). Structure-activity relationships were discussed with the analysis of lipophilic and spatial properties of the investigated compounds. Pharmacophore model of adenosine A1 receptor antagonist was adopted for this purpose. SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/17499511/N9_benzyl_substituted_13_dimethyl__and_13_dipropyl_pyrimido[21_f]purinediones:_synthesis_and_structure_activity_relationships_at_adenosine_A1_and_A2A_receptors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(07)00335-5 DB - PRIME DP - Unbound Medicine ER -