2-Substituted (N)-Methanocarba A Adenosine Receptor Agonists: In Silico, In Vitro, and In Vivo Characterization.

2-Arylethynyl (N)-methanocarba adenosine 5'-methylamides are selective A adenosine receptor (AR) agonists containing a preestablished receptor-preferred pseudoribose conformation. Here, we compare analogues having bulky 2-substitution, either containing or lacking an ethynyl spacer between adenine and a cyclic group. 2-Aryl compounds -, , , , , , , , , and , lacking a spacer, had human (h) AAR values of 2-30 nM, and others displayed lower affinity.

Histone H2A.Z Deacetylation and Dedifferentiation in Infarcted/Tip60-depleted Cardiomyocytes.

Myocardial infarction (MI) results in the loss of billions of cardiomyocytes (CMs), resulting in cardiac dysfunction. To re-muscularize injured myocardium, new CMs must be generated via renewed proliferation of surviving CMs. Approaches to induce proliferation of CMs after injury have been insufficient.

Extrahelical Binding Site for a 1-Imidazo[4,5-c]quinolin-4-amine A Adenosine Receptor Positive Allosteric Modulator on Helix 8 and Distal Portions of Transmembrane Domains 1 and 7.

This study describes the localization and computational prediction of a binding site for the A adenosine receptor (AAR) positive allosteric modulator 2-cyclohexyl-1-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix (H) 8, which was predicted by molecular modeling and validated by mutagenesis. According to the model, the nearly planar 1-imidazo[4,5-c]quinolinamine ring system lies parallel to the transmembrane segments, inserted into an aromatic cage formed by π-π stacking interactions with the side chains of Y284 in TMD7 and Y293 in H8 and by π-NH bonding between Y284 and the exocyclic amine.

First Potent Macrocyclic A Adenosine Receptor Agonists Reveal G-Protein and β-Arrestin2 Signaling Preferences.

()-Methanocarba adenosine derivatives (A adenosine receptor (AR) agonists containing bicyclo[3.1.0]hexane replacing furanose) were chain-extended at and C2 positions with terminal alkenes for ring closure.