Faculty Collaboration Database

Characterization of Dual-Acting A₃ Adenosine Receptor Positive Allosteric Modulators That Preferentially Enhance Adenosine-Induced Gα_i3 and Gα_oA Isoprotein Activation. ACS Pharmacol Transl Sci 2022 Aug 12;5(8):625-641

Date

08/20/2022

Pubmed ID

35983277

Pubmed Central ID

PMC9380209

DOI

10.1021/acsptsci.2c00076

Scopus ID

2-s2.0-85135593508 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

The A₃ adenosine receptor (A₃AR) is a promising therapeutic target for inflammatory diseases, cancer, and chronic neuropathic pain, with agonists already in advanced clinical trials. Here we report an in-depth comparison of the pharmacological properties and structure-activity relationships of existing and expanded compound libraries of 2-substituted 1H-imidazo[4,5-c]quinolin-4-amine and 4-amino-substituted quinoline derivatives that function as A₃AR positive allosteric modulators (PAMs). We also show that our lead compound from each series enhances adenosine-induced A₃AR signaling preferentially toward activation of Gα_i3 and Gα_oA isoproteins, which are coexpressed with the A₃AR in immune cells and spinal cord neurons. Finally, utilizing an extracellular/intracellular chimeric A₃AR approach composed of sequences from a responding (human) and a nonresponding (mouse) species, we provide evidence in support of the idea that the imidazoquinolin-4-amine class of PAMs variably interacts dually with the orthosteric ligand binding site as well as with a separate allosteric site located within the inner/intracellular regions of the receptor. This study has advanced both structural and pharmacological understanding of these two classes of A₃AR PAMs, which includes leads for future pharmaceutical development.

Author List

Fisher CL, Fallot LB, Wan TC, Keyes RF, Suresh RR, Rothwell AC, Gao ZG, McCorvy JD, Smith BC, Jacobson KA, Auchampach JA

Authors

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Robert Keyes PhD Research Scientist II in the Biochemistry department at Medical College of Wisconsin
John McCorvy PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Tina C. Wan PhD Research Scientist II in the Pediatrics department at Medical College of Wisconsin