N6-(Arylalkyl)adenosines. Identification of N6-(9-fluorenylmethyl)adenosine as a highly potent agonist for the adenosine A2 receptor

• Published in: Journal of medicinal chemistry Vol. 31; no. 1; pp. 271 - 273
• Main Authors: Trivedi, B. K, Bristol, J. A, Bruns, R. F, Haleen, S. J, Steffen, R. P
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.01.1988
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - metabolism; Animals; Brain - metabolism; Carbohydrates. Nucleosides and nucleotides; Cell Membrane - metabolism; Chemistry; Coronary Circulation - drug effects; Exact sciences and technology; Fluorenes - chemical synthesis; Fluorenes - metabolism; Heart Rate - drug effects; In Vitro Techniques; Indicators and Reagents; Kinetics; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Rats; Receptors, Purinergic - metabolism; Structure-Activity Relationship; Purine nucleoside; Ribonucleoside; Biological activity; Biological receptor
• DOI: 10.1021/jm00396a044
• ISSN: 0022-2623

Several N6-(arylalkyl)adenosines related to N6-benzyladenosine were synthesized, and their A1 and A2 adenosine receptor binding affinities were determined. The annulated derivative N6-(1-naphthylmethyl)adenosine resulted in a very potent A2 agonist (A1 Ki = 24 nM, A2 Ki = 9.1 nM), whereas N6-(9-anthracenylmethyl)adenosine was virtually inactive (A1 Ki = 9,000 nM, A2 Ki = 29,000 nM). Interestingly, the structurally similar N6-(9-fluorenylmethyl)adenosine was the most potent A2 agonist reported to date, with a Ki of 4.9 nM in A2 binding and 5.1 nM in A1 binding. The homologues N6-9-fluorenyladenosine and N6-[2-(9-fluorenyl)ethyl]adenosine showed little or no activity at either adenosine receptor. Effects of these agents on heart rate and coronary flow in the isolated rat heart paralleled their A1 and A2 binding affinities, respectively. These data suggest that for high affinity at the A2 receptor a planar hydrophobic function at a certain distance and angle from the N6 nitrogen is required.