Characterization of Dual-Acting A Adenosine Receptor Positive Allosteric Modulators That Preferentially Enhance Adenosine-Induced Gα and Gα Isoprotein Activation

Overview

Journal ACS Pharmacol Transl Sci

Publisher American Chemical Society

Specialty Biochemistry

Date 2022 Aug 19

PMID 35983277

Authors

Courtney L Fisher

Lucas B Fallot

Tina C Wan

Robert F Keyes

R Rama Suresh

Amy C Rothwell

Zhan-Guo Gao

John D McCorvy

Brian C Smith

Kenneth A Jacobson

John A Auchampach

Affiliations

Soon will be listed here.

Abstract

The A adenosine receptor (AAR) 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 1-imidazo[4,5-]quinolin-4-amine and 4-amino-substituted quinoline derivatives that function as AAR positive allosteric modulators (PAMs). We also show that our lead compound from each series enhances adenosine-induced AAR signaling preferentially toward activation of Gα and Gα isoproteins, which are coexpressed with the AAR in immune cells and spinal cord neurons. Finally, utilizing an extracellular/intracellular chimeric AAR 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 AAR PAMs, which includes leads for future pharmaceutical development.

Citing Articles

Lipid Trolling to Optimize A Adenosine Receptor-Positive Allosteric Modulators (PAMs).

Pradhan B, Pavan M, Fisher C, Salmaso V, Wan T, Keyes R J Med Chem. 2024; 67(14):12221-12247.

PMID: 38959401 PMC: 11636968. DOI: 10.1021/acs.jmedchem.4c00944.

Extrahelical Binding Site for a 1-Imidazo[4,5-c]quinolin-4-amine A Adenosine Receptor Positive Allosteric Modulator on Helix 8 and Distal Portions of Transmembrane Domains 1 and 7.

Fisher C, Pavan M, Salmaso V, Keyes R, Wan T, Pradhan B Mol Pharmacol. 2024; 105(3):213-223.

PMID: 38182432 PMC: 10877738. DOI: 10.1124/molpharm.123.000784.

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

Tosh D, Fisher C, Salmaso V, Wan T, Campbell R, Chen E ACS Pharmacol Transl Sci. 2023; 6(9):1288-1305.

PMID: 37705595 PMC: 10496144. DOI: 10.1021/acsptsci.3c00126.

New paradigms in purinergic receptor ligand discovery.

Jacobson K, Pradhan B, Wen Z, Pramanik A Neuropharmacology. 2023; 230:109503.

PMID: 36921890 PMC: 10233512. DOI: 10.1016/j.neuropharm.2023.109503.

Species dependence of A adenosine receptor pharmacology and function.

Gao Z, Auchampach J, Jacobson K Purinergic Signal. 2022; 19(3):523-550.

PMID: 36538251 PMC: 9763816. DOI: 10.1007/s11302-022-09910-1.

References

van der Hoeven D, Wan T, Auchampach J . Activation of the A(3) adenosine receptor suppresses superoxide production and chemotaxis of mouse bone marrow neutrophils. Mol Pharmacol. 2008; 74(3):685-96. PMC: 2574951. DOI: 10.1124/mol.108.048066. View

Tosh D, Paoletta S, Chen Z, Crane S, Lloyd J, Gao Z . Structure-Based Design, Synthesis by Click Chemistry and Activity of Highly Selective A Adenosine Receptor Agonists. Medchemcomm. 2015; 6:555-563. PMC: 4517612. DOI: 10.1039/C4MD00571F. View

Fishman P, Cohen S, Itzhak I, Amer J, Salhab A, Barer F . The A3 adenosine receptor agonist, namodenoson, ameliorates non‑alcoholic steatohepatitis in mice. Int J Mol Med. 2019; 44(6):2256-2264. PMC: 6844636. DOI: 10.3892/ijmm.2019.4364. View

Singh A, Mahalingam R, Squillace S, Jacobson K, Tosh D, Dharmaraj S . Targeting the A adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice. Acta Neuropathol Commun. 2022; 10(1):11. PMC: 8800287. DOI: 10.1186/s40478-022-01315-w. View

Cong Z, Chen L, Ma H, Zhou Q, Zou X, Ye C . Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. Nat Commun. 2021; 12(1):3763. PMC: 8213797. DOI: 10.1038/s41467-021-24058-z. View

Kuwano Y, Adler M, Zhang H, Groisman A, Ley K . Gαi2 and Gαi3 Differentially Regulate Arrest from Flow and Chemotaxis in Mouse Neutrophils. J Immunol. 2016; 196(9):3828-33. PMC: 4868657. DOI: 10.4049/jimmunol.1500532. View

Gao Z, Suresh R, Jacobson K . Pharmacological characterization of DPTN and other selective A adenosine receptor antagonists. Purinergic Signal. 2021; 17(4):737-746. PMC: 8677861. DOI: 10.1007/s11302-021-09823-5. View

Ge Z, Peart J, Kreckler L, Wan T, Jacobson M, Gross G . Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor. J Pharmacol Exp Ther. 2006; 319(3):1200-10. DOI: 10.1124/jpet.106.111351. View

. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature. 2018; 562(7727):367-372. PMC: 6642641. DOI: 10.1038/s41586-018-0590-4. View

10.

Durante M, Squillace S, Lauro F, Giancotti L, Coppi E, Cherchi F . Adenosine A3 agonists reverse neuropathic pain via T cell-mediated production of IL-10. J Clin Invest. 2021; 131(7). PMC: 8011899. DOI: 10.1172/JCI139299. View

11.

Du L, Gao Z, Paoletta S, Wan T, Gizewski E, Barbour S . Species differences and mechanism of action of A adenosine receptor allosteric modulators. Purinergic Signal. 2017; 14(1):59-71. PMC: 5842153. DOI: 10.1007/s11302-017-9592-1. View

12.

Coughlin Q, Hopper A, Blanco M, Tirunagaru V, Robichaud A, Doller D . Allosteric Modalities for Membrane-Bound Receptors: Insights from Drug Hunting for Brain Diseases. J Med Chem. 2019; 62(13):5979-6002. DOI: 10.1021/acs.jmedchem.8b01651. View

13.

Desai A, Mechin I, Nagarajan K, Valant C, Wootten D, Lam P . Molecular Basis of Action of a Small-Molecule Positive Allosteric Modulator Agonist at the Type 1 Cholecystokinin Holoreceptor. Mol Pharmacol. 2018; 95(3):245-259. DOI: 10.1124/mol.118.114082. View

14.

Chan H, Li Y, Dahoun T, Vogel H, Yuan S . New Binding Sites, New Opportunities for GPCR Drug Discovery. Trends Biochem Sci. 2019; 44(4):312-330. DOI: 10.1016/j.tibs.2018.11.011. View

15.

Kim Y, de Castro S, Gao Z, IJzerman A, Jacobson K . Novel 2- and 4-substituted 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the A3 adenosine receptor. J Med Chem. 2009; 52(7):2098-108. PMC: 2765805. DOI: 10.1021/jm801659w. View

16.

Slosky L, Caron M, Barak L . Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery. Trends Pharmacol Sci. 2021; 42(4):283-299. PMC: 9797227. DOI: 10.1016/j.tips.2020.12.005. View

17.

Draper-Joyce C, Bhola R, Wang J, Bhattarai A, Nguyen A, Cowie-Kent I . Positive allosteric mechanisms of adenosine A receptor-mediated analgesia. Nature. 2021; 597(7877):571-576. PMC: 8711093. DOI: 10.1038/s41586-021-03897-2. View

18.

Little J, Ford A, Symons-Liguori A, Chen Z, Janes K, Doyle T . Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain. 2014; 138(Pt 1):28-35. PMC: 4285194. DOI: 10.1093/brain/awu330. View

19.

Ge Z, van der Hoeven D, Maas J, Wan T, Auchampach J . A(3) adenosine receptor activation during reperfusion reduces infarct size through actions on bone marrow-derived cells. J Mol Cell Cardiol. 2010; 49(2):280-6. PMC: 2885516. DOI: 10.1016/j.yjmcc.2010.01.018. View

20.

Deganutti G, Cuzzolin A, Ciancetta A, Moro S . Understanding allosteric interactions in G protein-coupled receptors using Supervised Molecular Dynamics: A prototype study analysing the human A3 adenosine receptor positive allosteric modulator LUF6000. Bioorg Med Chem. 2015; 23(14):4065-71. DOI: 10.1016/j.bmc.2015.03.039. View