2-Amino-5-arylethynyl-thiophen-3-yl-(phenyl)methanones as A1 Adenosine Receptor Positive Allosteric Modulators

A₁ Adenosine Receptor (A₁AR) agonists have cerebroprotective, cardioprotective, antinociceptive, and Other pharmaceutical applications. We explored the structure-activity relationship of 5-arylethynyl aminothiophenes as A₁AR positive allosteric modulators (PAMs). The derivatives were compared in binding and functional assays at the human A₁AR, indicating that some fluoro-substituted analogues have enhanced PAM activity. We identified substitution of the terminal phenyl ring in 12 (2-F-Ph), 15 (3,4-F₂-Ph, MRS7935), and 21 (2-CF₃-Ph) as particularly enhancing the PAM activity. 15 was also shown to act as an A₁ ago-PAM with EC₅₀ ≈ 2 μM, without activity (30 μM) at Other ARs. Molecular modeling indicated that both the 5-arylethynyl and the 4-neopentyl groups are located in a region outside the receptor transmembrane helix bundle that is in contact with the phospholipid bilayer, consistent with the preference for nonpolar substitution of the aryl moiety. Although they are hydrophobic, these PAMs could provide potential drug candidate molecules for engaging protective A₁ARs.