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First Potent Macrocyclic A 3 Adenosine Receptor Agonists Reveal G-Protein and β-Arrestin2 Signaling Preferences.

Dilip K ToshCourtney L FisherVeronica SalmasoTina C WanRyan G CampbellEric ChenZhan-Guo GaoJohn A AuchampachKenneth A Jacobson
Published in: ACS pharmacology & translational science (2023)
( N )-Methanocarba adenosine derivatives (A 3 adenosine receptor (AR) agonists containing bicyclo[3.1.0]hexane replacing furanose) were chain-extended at N 6 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 A 3 AR-selective than 2-ether-linked macrocycle 12 (both 5'-methylamides, human (h) A 3 AR affinities ( K i ): 22.1 and 25.8 nM, respectively), with lower mouse A 3 AR affinities. Functional hA 3 AR comparison of two sets of open/closed analogues in β-arrestin2 and G i/o protein assays showed certain signaling preferences divergent from reference agonist Cl-IB-MECA 1 . The potencies of 1 at all three Gα i isoforms were slightly less than its hA 3 AR binding affinity ( K i : 1.4 nM), while the Gα i1 and Gα i2 potencies of macrocycle 12 were roughly an order of magnitude higher than its radioligand binding affinity. Gα i2 -coupling was enhanced in macrocycle 12 (EC 50 2.56 nM, ∼40% greater maximal efficacy than 1 ). Di-O-allyl precursor 18 cyclized to form 19 , increasing the Gα i1 potency by 7.5-fold. The macrocycles 12 and 19 and their open precursors 11 and 18 potently stimulated β-arrestin2 recruitment, with EC 50 values (nM) of 5.17, 4.36, 1.30, and 4.35, respectively, and with nearly 50% greater efficacy compared to 1 . This example of macrocyclization altering the coupling pathways of small-molecule (nonpeptide) GPCR agonists is the first for potent and selective macrocyclic AR agonists. These initial macrocyclic derivatives can serve as a guide for the future design of macrocyclic AR agonists displaying unanticipated pharmacology.
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