Effect of Linker Length and Composition on Heterobivalent Ligand‐Mediated Receptor Cross‐Talk between the A₁ Adenosine and β₂ Adrenergic Receptors

Abstract

Heterobivalent ligands that possess pharmacophores designed to interact with both the A1 adenosine receptor (A1 AR) and the β2 adrenergic receptor (β2 AR) were prepared. More specifically, these ligands contain an adenosine moiety that is linked via its N(6) -position to the amino group of the saligenin-substituted ethanolamine moiety present in the well-known β2 AR agonist, salbutamol. The affinities of these ligands were determined at both receptors and found to vary with linker length and composition. With all compounds, affinity and functional potencies were found to have selectivity for the A1 AR over the β2 AR. In all cases, cAMP accumulation (a β2 AR-mediated response) was mainly observed when the A1 AR was blocked or its function decreased by pertussis toxin or chronic agonist treatment. This suggests that heterobivalent compounds for receptors that mediate opposite responses might be useful for elucidating the mechanisms of receptor cross-talk and how this interaction, in terms of responsiveness, may change under pathophysiological conditions.

2016 Philip S. Portoghese Medicinal Chemistry Lectureship: Designing Bivalent or Bitopic Molecules for G-Protein Coupled Receptors. The Whole Is Greater Than the Sum of Its Parts

“…Indeed, the prevalence of heteromers within the adrenergic receptor systems − makes them interesting targets for the treatment of various cardiovascular ailments. − For example, Karellas et al introduced heterobivalent molecules targeting β2-adrenergic receptor/adenosine A 1 receptor (β 2 AR/A 1 AR) heteromers in an effort to understand the cross talk among these two cellular cAMP regulating receptors; it was proposed that careful balance between the signaling pathways generated by the two receptor monomers conforming this heteromer could aid in the prevention of certain cardiac arrhythmias . Due to the importance of functions regulated by this receptor system, it has become the focus of significant analysis via heterobivalent ligands …”

“…47 Due to the importance of functions regulated by this receptor system, it has become the focus of significant analysis via heterobivalent ligands. 49 The study of dopamine receptor heteromers with the use of heterobivalent ligands is equally promising. Adenosine A 2A receptor (A 2A R) and dopamine D 2 receptor heteromers (D 2 R/ A 2A R) are of particular interest due to their purported role in Parkinson's disease.…”

The size matters? A computational tool to design bivalent ligands

“…Many studies have reported spacers between 15 and 25 atoms such as ligands targeting dimers of the δ- and μ-opioid ( Fig. 1 , molecule 1 ) ( Daniels et al , 2005 ), serotonin ( 2 ) ( Soulier et al , 2005 ), dopamine ( 3 and 4 ) ( Kuhhorn et al , 2011 ; McRobb et al , 2012 ), cannabinoid and μ opioid/cannabinoid ( 5 and 6 ) ( Le Naour et al , 2013 ; Zhang et al , 2010 ), A 2A -D 2 ( 8 ) ( Soriano et al , 2009 ) and A 1 -β 2 ( 9 ) ( Barlow et al , 2013 ) (homo/hetero)dimers to name just a few. Recently, highly active ligands with spacers as large as 44 and 66 atoms ( 7 ) ( Hubner et al , 2016 ) were reported.…”

Rational Modification of the Biological Profile of GPCR Ligands through Combination with Other Biologically Active Moieties

“…The bivalency approach led to ligands with increased affinity or better selectivity toward receptor subtypes. Bivalent ligands have been developed for many GPCRs, such as opioid , adrenergic , dopamine , serotonin , and muscarinic receptor subtypes. In some cases, bivalent ligands were confirmed to bind to dimeric receptors, such as dopamine receptor dimers .…”