5‘-O-Alkyl Ethers of N,2-Substituted Adenosine Derivatives:  Partial Agonists for the Adenosine A1 and A3 Receptors

• Published in: Journal of medicinal chemistry Vol. 44; no. 18; pp. 2966 - 2975
• Main Authors: van Tilburg, Erica W, van der Klein, Pieter A. M, von Frijtag Drabbe Künzel, Jacobien, de Groote, Miriam, Stannek, Christina, Lorenzen, Anna, IJzerman, Ad P
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 30-08-2001
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - metabolism; Adenosine - pharmacology; Animals; Binding, Competitive; Biological and medical sciences; Cell Line; Cerebral Cortex - metabolism; Cricetinae; Cyclic AMP - biosynthesis; Humans; In Vitro Techniques; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Purinergic P1 Receptor Agonists; Radioligand Assay; Rats; Receptor, Adenosine A3; Receptors, Purinergic P1 - metabolism; Structure-Activity Relationship; Human; Partial agonist; Purine nucleoside; Structure activity relation; Chlorine Organic compounds; A1 Adenosine receptor; Affinity; Selectivity; Ribonucleoside; Chemical synthesis; Iodine Organic compounds; In vitro
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm001114o

New N,5‘-di- and N,2,5‘-trisubstituted adenosine derivatives were synthesized in good overall yields. Appropriate 5-O-alkyl-substituted ribose moieties were coupled to 6-chloropurine or 2,6-dichloropurine via Vorbrüggen's glycosylation method. Subsequent amination and deprotection of the intermediates yielded compounds 18 − 35. Binding affinities were determined for rat adenosine A1 and A2A receptors and the human A3 receptor. The ability of compounds 18 − 35 to inhibit forskolin-induced (10 μM) cyclic AMP (cAMP) production and their ability to stimulate guanosine 5‘-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding, via either the adenosine A1 receptor or the adenosine A3 receptor, were assessed. N-Cyclopentyl-substituted adenosine derivatives displayed affinities in the low nanomolar range for the adenosine A1 receptor, whereas N-(3-iodobenzyl)-substituted derivatives had high affinity for the adenosine A3 receptor. Compound 22 had the highest affinity for the adenosine A1 receptor (K i value of 16 nM), and compounds 20 and 26 had the highest affinities for the adenosine A3 receptor (K i values of 4 and 3 nM, respectively). A chlorine substituent at the 2-position either did not affect or slightly increased the adenosine A1 receptor affinity, whereas the A3 receptor affinity was affected differently, depending on the N-substituent. Furthermore, the introduction of chlorine slightly increased the A3/A1 selectivity ratio. At the 5‘-position, an O-methyl substituent induced the highest adenosine A1 receptor affinity, whereas an O-ethyl substituent did so for the A3 receptor. All compounds showed partial agonistic effects in both the cAMP and [35S]GTPγS assays, although more marked in the latter assay. In general, the 2-chloro derivatives seemed to have lower intrinsic activities compared to the 2-H-substituted compounds on both the adenosine A1 and the adenosine A3 receptors. The compounds with an N-(3-iodobenzyl) substituent displayed the lowest intrinsic activities. Finally, all compounds also showed partially antagonistic behavior in the [35S]GTPγS assay.