First Potent Macrocyclic A₃ Adenosine Receptor Agonists Reveal G-Protein and β-Arrestin2 Signaling Preferences.

ABSTRACT: (N)-Methanocarba adenosine derivatives (A₃ adenosine receptor (AR) agonists containing bicyclo[3.1.0]hexane replacing furanose) were chain-extended at N⁶ and C2 positions with terminal alkenes for ring closure. The resulting macrocycles of 17-20 atoms retained affinity, indicating a spatially proximal orientation of these receptor-bound chains, consistent with molecular modeling of 12. C2-Arylethynyl-linked macrocycle 19 was more A₃AR-selective than 2-ether-linked macrocycle 12 (both 5'-methylamides, human (h) A₃AR affinities (K_i): 22.1 and 25.8 nM, respectively), with lower mouse A₃AR affinities. Functional hA₃AR comparison of two sets of open/closed analogues in β-arrest

SUBMITTER: Tosh DK 

PROVIDER: S-EPMC10496144 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature