Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human A3 Adenosine Receptors: Affinity Enhancement by N6-(2-Phenylethyl) Substitution. J Med Chem 2020 Apr 23;63(8):4334-4348
Date
04/10/2020Pubmed ID
32271569Pubmed Central ID
PMC7443318DOI
10.1021/acs.jmedchem.0c00235Scopus ID
2-s2.0-85083291207 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
Dopamine-derived N6-substituents, compared to N6-(2-phenylethyl), in truncated (N)-methanocarba (bicyclo[3.1.0]hexyl) adenosines favored high A3 adenosine receptor (AR) affinity/selectivity, e.g., C2-phenylethynyl analogue 15 (MRS7591, Ki = 10.9/17.8 nM, at human/mouse A3AR). 15 was a partial agonist in vitro (hA3AR, cAMP inhibition, 31% Emax; mA3AR, [35S]GTP-γ-S binding, 16% Emax) and in vivo and also antagonized hA3AR in vitro. Distal H-bonding substitutions of the N6-(2-phenylethyl) moiety particularly enhanced mA3AR affinity by polar interactions with the extracellular loops, predicted using docking and molecular dynamics simulation with newly constructed mA3AR and hA3AR homology models. These hybrid models were based on an inactive antagonist-bound hA1AR structure for the upper part of TM2 and an agonist-bound hA2AAR structure for the remaining TM portions. These species-independent A3AR-selective nucleosides are low efficacy partial agonists and novel, nuanced modulators of the A3AR, a drug target of growing interest.
Author List
Tosh DK, Salmaso V, Rao H, Bitant A, Fisher CL, Lieberman DI, Vorbrüggen H, Reitman ML, Gavrilova O, Gao ZG, Auchampach JA, Jacobson KAAuthor
John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adenosine A3 Receptor AgonistsAnimals
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nucleosides
Protein Binding
Protein Structure, Secondary
Receptor, Adenosine A3
