Key result
A1 adenosine receptor agonists are under development for atrial arrhythmias, type 2 diabetes, pain, and angina, with new partial agonists potentially avoiding cardiovascular side effects.
A1 adenosine receptor agonists are under active development for conditions including atrial arrhythmias and angina, with newer partial agonists designed to overcome historical challenges of tachyphylaxis and off-target cardiovascular effects.
Answers are grounded in this paper and cite their sources.
Supports preclinical development of partial A1 agonists; hypothesis-generating until human trials confirm safety and efficacy.
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.
No takes yet. Share an insight, caveat, or question.
Elzein et al. (2008) conducted a review in Atrial arrhythmias, type 2 diabetes, pain management, and angina. A1 adenosine receptor agonists was evaluated. A1 adenosine receptor agonists are under development for atrial arrhythmias, type 2 diabetes, pain, and angina, with new partial agonists potentially avoiding cardiovascular side effects.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: