2-(Arylalkylamino)adenosin-5'-uronamides: a new class of highly selective adenosine A2 receptor ligands

• Published in: Journal of medicinal chemistry Vol. 33; no. 7; pp. 1919 - 1924
• Main Authors: Hutchison, Alan J, Williams, Michael, De Jesus, Reynalda, Yokoyama, Rina, Oei, Howard H, Ghai, Geetha R, Webb, Randy L, Zoganas, Harry C, Stone, George A, Jarvis, Michael F
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.07.1990
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - pharmacology; Animals; Brain - metabolism; Carbohydrates. Nucleosides and nucleotides; Chemistry; Coronary Circulation - drug effects; Exact sciences and technology; Heart Rate - drug effects; In Vitro Techniques; Indicators and Reagents; Ligands; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Rats; Rats, Inbred Strains; Receptors, Purinergic - metabolism; Structure-Activity Relationship; Vasodilation - drug effects; Agonist; Purine nucleoside; Structure activity relation; Uronic acid; Affinity; Carboxamide; Adenosine receptor; Ribonucleoside
• DOI: 10.1021/jm00169a015
• ISSN: 0022-2623

The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.