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• W4377020141 abstract "<b>Abstract ID 14834</b> <b>Poster Board 514</b> The A₃ adenosine receptor (A₃AR) is a therapeutic target for inflammatory diseases, ischemia, cancer, neuropathic pain, liver diseases and other chronic conditions [1]. Most reported clinical and preclinical candidate molecules acting selectively at this G protein-coupled receptor (GPCR) are agonists of the nucleoside class. Macrocyclic derivatives of small molecules, often derived from natural products, are used increasingly in medicinal chemistry to improve absorption or to maintain conformational control to enable interaction with a target biomolecule. (N)-Methanocarba adenosine derivatives (A₃AR agonists containing bicyclo[3.1.0]hexane replacing furanose) were synthesized with chains extended at <i>N</i>⁶ and C2 positions with terminal alkenes for ring closure, and the compounds compared in both binding and functional assays. The resulting macrocycles of 17–20 atoms retained A₃ affinity in radioligand binding, indicating a spatially proximal orientation of these chains when receptor-bound, consistent with molecular modeling. C2-Arylethynyl derivative <b>19</b> was more A₃AR-selective than 2-ether <b>12</b> (both 59-methylamides, human (h) A₃AR affinities (K_i) 22.1 and 25.8 nM, respectively). Functional hA₃AR comparison of two sets of open/closed analogues in b-arrestin2 and G_i/oprotein assays showed certain signaling preferences divergent from reference agonist Cl-IB-MECA. The potencies of Cl-IB-MECA at all three Ga_i isoforms were slightly less than its hA₃AR binding affinity (K_i 1.4 nM), while the Ga_i1 and Ga_i2 potencies of macrocycle <b>12</b> were roughly an order of magnitude higher than its radioligand binding affinity. Ga_i2-coupling was enhanced in macrocyclic derivative <b>12</b> (EC₅₀ 2.56 nM, ∼40% greater maximal efficacy than Cl-IB-MECA). Di-<i>O</i>-allyl derivative <b>18</b> cyclized to form <b>19</b>, increasing the Ga_i1 potency by 7.5-fold. The macrocycles <b>12</b> and <b>19</b> and their open precursors <b>11</b> and <b>18</b> potently stimulated b-arrestin2 recruitment, with EC₅₀ values (nM) of 5.17, 4.36, 1.30 and 4.35, respectively and with nearly 50% greater efficacy compared to <b>1</b>. This example of macrocyclization altering the coupling pathways of small molecule (non-peptide) 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. 1. Jacobson KA, Merighi, S, Varani, K, et al. (2018) A₃ adenosine receptors as modulators of inflammation: from medicinal chemistry to therapy. <i>Med Res Rev</i> 2018;38:1031-1072. <b>Support/Funding Information:</b> NIDDK (ZIADK031117); NHLBI R01 (HL133589)." @default.
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• W4377020141 date "2023-05-18" @default.
• W4377020141 modified "2023-10-15" @default.
• W4377020141 title "First potent macrocyclic A₃adenosine receptor agonists reveal G-protein and beta-arrestin2 signaling preferences" @default.
• W4377020141 doi "https://doi.org/10.1124/jpet.122.148340" @default.
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