A Structure–Activity Relationship Study of Bitopic N⁶-Substituted Adenosine Derivatives as Biased Adenosine A₁ Receptor Agonists

Abstract

The adenosine A receptor (AAR) is a potential novel therapeutic target for myocardial ischemia-reperfusion injury. However, to date, clinical translation of prototypical AAR agonists has been hindered due to dose limiting adverse effects. Recently, we demonstrated that the biased bitopic agonist 1, consisting of an adenosine pharmacophore linked to an allosteric moiety, could stimulate cardioprotective AAR signaling in the absence of unwanted bradycardia. Therefore, this study aimed to investigate the structure-activity relationship of compound 1 biased agonism. A series of novel derivatives of 1 were synthesized and pharmacologically profiled. Modifications were made to the orthosteric adenosine pharmacophore, linker, and allosteric 2-amino-3-benzoylthiophene pharmacophore to probe the structure-activity relationships, particularly in terms of biased signaling, as well as AAR activity and subtype selectivity. Collectively, our findings demonstrate that the allosteric moiety, particularly the 4-(trifluoromethyl)phenyl substituent of the thiophene scaffold, is important in conferring bitopic ligand bias at the AAR.

The effect of two selective A1‐receptor agonists and the bitopic ligand VCP746 on heart rate and regional vascular conductance in conscious rats

“…However, as predicted from the in vivo cardiovascular data obtained in the present manuscript, VCP746 was also a potent and high efficacy agonist of A 2A ‐mediated CRE‐SPAP responses. An agonist effect of VCP746 on cAMP formation at A 2A ‐receptors has also been reported recently in CHO cells (Aurelio et al, ).…”

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity

“… Moya et al (2007) examined functional selectivity profiles for a series of phenethylamine and phenylisopropylamine derivatives at human 5-HT 2A and 5-HT 2C receptors and found that subtle changes in ligand structure resulted in pronounced difference in cellular signaling profiles. These data highlight the need for careful ligand structure-functional selectivity relationship studies to improve our understanding of the molecular mechanisms that underlie functional selectivity ( Chen et al, 2012 ; Shonberg et al, 2013 ; Szabo et al, 2014 ; White et al, 2014 ; Chang et al, 2015 ; Lovell et al, 2015 ; Baltos et al, 2016 ; Manglik et al, 2016 ; Männel et al, 2017 ; Aurelio et al, 2018 ; Chun et al, 2018 ).…”

Biased Receptor Signaling in Drug Discovery

“…If a quantitative scale of bias is employed then a simple correlation of DDLog(t/K A ) values can be useful. Figure 12 shows DDLog(t/K A ) values for a series of bitopic adenosine A 1 receptor agonists (referenced to NECA [1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-b-Dribofuranuronamide]) for calcium and cAMP responses; it can be seen that while eight compounds correlate fairly well [uniform DDLog(t/K A ) values], the eight compounds in red are biased toward cAMP over calcium (Aurelio et al, 2018). Other methods are used if more than one signaling pathway is involved.…”

“…Agonists denoted with black solid circles show uniform activation of both pathways (no bias), whereas circles in red indicate bias toward cAMP signaling over calcium. Data redrawn fromAurelio et al (2018).…”