5‘-Deoxy Congeners of 9-(3-Amido-3-deoxy-β-d -xylofuranosyl)-N6-cyclopentyladenine: New Adenosine A1 Receptor Antagonists and Inverse Agonists
| Autor: | Veerle Vanheusden, Abolfasl Golisade, Norbert Blaton, Rianne A. F. de Ligt, Jef Rozenski, Piet Herdewijn, and Adriaan P. IJzerman, Andreas Link, Shelly Fujikawa, Serge Van Calenbergh |
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| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular medicine.drug_class Stereochemistry Carboxamide CHO Cells In Vitro Techniques Crystallography X-Ray Binding Competitive Chemical synthesis Radioligand Assay Structure-Activity Relationship Adenosine A1 receptor chemistry.chemical_compound Deoxyadenosine Cricetinae Drug Discovery Cyclic AMP Purinergic P1 Receptor Agonists medicine Animals Humans Inverse agonist Moiety Structure–activity relationship Deoxyadenosines Chemistry Receptors Purinergic P1 Adenosine receptor Rats Purinergic P1 Receptor Antagonists Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 45:1845-1852 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The synthesis and structure-activity relationship of N(6)-cyclopentyl-3'-substituted-xylofuranosyladenosine analogues with respect to various adenosine receptors were explored in order to identify selective and potent antagonists and inverse agonists for the adenosine A(1) receptor. In particular, the effects of removal of the 5'-OH group and introduction of selected substituents at the 3'-NH(2) position of 9-(3-amino-3-deoxy-beta-D-xylofuranosyl)-N(6)-cyclopentyladenine were probed. A solid phase-assisted synthetic approach was used to optimize the 3'-amide functionality. In view of the general concern of the presence of a 5'-OH moiety with regard to cellular toxicity, the present study describes 5'-deoxy compounds with reasonable affinity for the human adenosine A(1) receptor. Interestingly, this study shows that optimization of the 3'-"up" amide substituent can substantially compensate for the drop in affinity for the adenosine A(1) receptor, which is generally observed upon removal of the 5'-OH group. The fact that for several 3'-amido-substituted (5'-deoxy)-N(6)-cyclopentyladenosine derivatives, guanosine 5'-triphosphate-induced shifts in K(i) values were significantly lower than 1 implies that these analogues behave as inverse agonists. This is further supported by their 1,3-dipropyl-8-cyclopentylxanthine-like capacity to increase forskolin-induced adenosine cyclic 3',5'-phosphate production. |
| Databáze: | OpenAIRE |
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