Adenosine is a physiological extracellular modulator acting via four distinct G protein-coupled receptors. A1 adenosine receptor (A1AR) agonists have cerebroprotective, cardioprotective, antinociceptive, and other pharmaceutical applications. Our goal was to design and synthesize a new series of thiophene derivatives able to bind the allosteric site of the A1AR with both tissue-specific and receptor-specific modulation capabilities. Most potent synthesized compounds were identified in biological saturation and competition assays using the human A1AR. We explored the structure-activity relationships of novel aminothiophenes derivatives as A1AR positive allosteric modulators (PAMs). We noticed that the activity of these compounds can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Also, the presence of the 4-neopentyl substitution can further enhance activity. Lastly, we also included a 5-arylethynyl substitution of the thiophene moiety to determine if it adds any further benefits to the PAM activity. The derivatives were compared in binding (saturation and competition) assays at the human A1AR and in functional cAMP studies. The most potent analogues contained 2-F, 3,4-F2, and 2-CF3 substitutions of the 5-terminal phenyl ring. These compounds achieved a strong PAM enhancement effect, each increasing the Bmax shift by ~73%, compared to the reference compound with ~77%. Lastly, molecular modeling analysis allowed us to predict molecular details of binding with the identification of key interactions. A1AR PAMs represent potential new drug molecules. It is our interest to further investigate the pharmacokinetic properties of our compounds and in vivo studies as possible candidates in the treatment of neuropathic pain, hypoxia, and ischemia-induced injury.

Structure-activity relationship of 5-arylethynyl derivatives of (2-aminothiophen-3-yl)(phenyl)methanones as A1 adenosine receptor positive allosteric modulators

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