A1 adenosine receptor agonists and their potential therapeutic applications

Expert Opin Investig Drugs. 2008 Dec;17(12):1901-10. doi: 10.1517/13543780802497284.


Background: The challenges in developing any A(1) adenosine receptor (A(1)-AdoR) agonist involve having the desired effect on target tissue while avoiding side effects due to activation of A(1)-AdoR on other tissues. A(1)-AdoR de-sensitization leading to tachyphylaxis is also another challenge.

Objectives: The major goal of this review is twofold: to highlight the structure affinity relationships (SAR) of A(1)-AdoR agonists, starting with initial lead compounds that were the genesis for second-generation compounds with high selectivity, affinity, and partial agonism; and to give an overview of the A(1)-AdoR agonists under development for various indications.

Results: Intense efforts by many pharmaceutical companies and academicians in the A(1)-AdoR agonist field have led to the discovery of clinical candidates for the following conditions: atrial arrhythmias - Tecadenoson, Selodenoson and PJ-875; type 2 diabetes (T2D) and insulin-sensitizing agents - GR79236, ARA, and CVT-3619; pain management - SDZ WAG 994, GW493838; and angina - BAY-68-4986. For the i.v. antiarrhythmic agents that act as ventricular rate control agents, a selective response can be accomplished by careful dosing paradigms. The treatment of T2D using A(1)-AdoR agonists has been met by limited success due to cardiovascular side effects and well-defined desensitization of full agonists in both animal models and human trials (GR79236 and ARA). However, new partial A(1)-AdoR agonists are in development, including CVT-3619 (hA(1)-AdoR K(i) = 55 nm, selectivity A(2A) > 200; A(2B) > 1000; A(3) > 20, CV Therapeutics), that have the potential to provide enhanced insulin sensitivity without cardiovascular side effects or tachyphylaxis. The A(1)-AdoR agonists GW493838 and GR792363 are under evaluation for pain management. The non-nucleosidic A(1)-AdoR agonist, BAY-68-4986 (Capadenoson), represents a unique approach to angina wherein both animal studies and early human studies are promising.

Conclusion: The challenges associated with developing an A(1)-AdoR agonist for therapeutic intervention are now well defined in humans. Significant progress has been made in identifying agents for the treatment of atrial arrhythmias, T2D, and angina.

Publication types

  • Review

MeSH terms

  • Adenosine A1 Receptor Agonists*
  • Aminopyridines*
  • Angina Pectoris / drug therapy
  • Animals
  • Anti-Arrhythmia Agents / chemistry
  • Anti-Arrhythmia Agents / therapeutic use
  • Humans
  • Insulin / metabolism
  • Pain / drug therapy
  • Receptor, Adenosine A1 / metabolism
  • Thiazoles*


  • Adenosine A1 Receptor Agonists
  • Aminopyridines
  • Anti-Arrhythmia Agents
  • Insulin
  • Receptor, Adenosine A1
  • Thiazoles
  • capadenoson