Structure—Affinity Relationships of 5′‐Aromatic Ethers and 5′‐Aromatic Sulfides as Partial A₁ Adenosine Agonists, Potential Supraventricular anti‐Arrhythmic Agents.

Abstract

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Optimization of Adenosine 5′-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening

“…It is to be noted that the hA 3 AR subtype harbors much more dramatic differences compared to both hA 1 AR and hA 2A AR among residues controlling the 5′ subpocket, including Q89H, N181S, and H250S substitutions. These changes, generally from larger to smaller polar side chains, apparently result in a more spacious subpocket in A 3 AR than in A 2A and A 1 subtypes, which is also in agreement with much bulkier 5′ substitutions being allowed for high-affinity A 3 AR selective agonists …”

A1adenosine receptor agonists and their potential therapeutic applications

“…In general, the 5′-aromatic ethers had greater affinity and potency for the A 1 -AdoR than the corresponding 5′-sulfides, and obviously 5′-substitution caused significant drop in affinity for the A 1 -AdoR when compared to Tecadenoson. Comparing the two lead molecules from both series ( 1 and 2 ), the aromatic ether analog 1 displayed higher affinity for the A 1 -AdoR ( K i = 12 nm) and sixfold greater potency (EC 50 = 200 nm) in slowing AV nodal conduction than 2 without causing third-degree AV block [39] . In addition, compound 1 exhibited greater oral bioavailability (81%) relative to 2 .…”

“…Scientists from CV Therapeutics have reported a number of partial A 1 -AdoR agonists as potential oral antiarrhythmic agents that do not cause high-degree AV block at high concentrations [39] . These new analogs were obtained by incorporating aromatic ethers and sulfides in the 5′-position of the full agonist Tecadenoson, a strategy that is known to decrease intrinsic activity with respect to GTP shift and induction of [ 35 S]GTP γ S binding to G protein [40] .…”

Adenosine A2A Receptor as a Drug Discovery Target

“…Although N6 substitution is tolerated, it generally decreases A 2A potency. In many cases, N6 substituents can actually enhance A 1 and A 3 affinity and selectivities. , This is exemplified by N 6-(tetrahydrofuryl)adenosine (tecadenoson), which is a potent A 1 -selective agonist. , …”