Selective A Adenosine Receptor Antagonist Radioligand for Human and Rodent Species

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Apr 22

PMID 35450351

Authors

R Rama Suresh

Zhan-Guo Gao

Veronica Salmaso

Eric Chen

Ryan G Campbell

Russell B Poe

Theodore E Liston

Kenneth A Jacobson

Affiliations

Soon will be listed here.

Abstract

The A adenosine receptor (AAR) is a target for pain, ischemia, and inflammatory disease therapy. Among the ligand tools available are selective agonists and antagonists, including radioligands, but most high-affinity non-nucleoside antagonists are limited in selectivity to primate species. We have explored the structure-activity relationship of a previously reported AAR antagonist DPTN (-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide) for radiolabeling, including 3-halo derivatives (3-iodo, MRS7907), and characterized as a high -affinity radioligand [H]MRS7799. AAR values were (nM): 0.55 (human), 3.74 (mouse), and 2.80 (rat). An extended methyl acrylate (MRS8074, ) maintained higher affinity (18.9 nM) than a 3-((5-chlorothiophen-2-yl)ethynyl) derivative . Compound had an excellent brain distribution in rats (brain/plasma ratio ∼1). Receptor docking predicted its orthosteric site binding by engaging residues that were previously found to be essential for AR binding. Thus the new radioligand promises to be a useful species-general antagonist tracer for receptor characterization and drug discovery.

Citing Articles

Assay-Dependent Inverse Agonism at the A Adenosine Receptor: When Neutral Is Not Neutral.

Pottie E, Suresh R, Jacobson K, Stove C ACS Pharmacol Transl Sci. 2023; 6(9):1266-1274.

PMID: 37705594 PMC: 10496142. DOI: 10.1021/acsptsci.3c00071.

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.

Structure-Activity Studies of 1-Imidazo[4,5-]quinolin-4-amine Derivatives as A Adenosine Receptor Positive Allosteric Modulators.

Fallot L, Suresh R, Fisher C, Salmaso V, OConnor R, Kaufman N J Med Chem. 2022; 65(22):15238-15262.

PMID: 36367749 PMC: 10354740. DOI: 10.1021/acs.jmedchem.2c01170.

Fluorescent A and A adenosine receptor antagonists as flow cytometry probes.

Toti K, Campbell R, Lee H, Salmaso V, Suresh R, Gao Z Purinergic Signal. 2022; 19(3):565-578.

PMID: 35687212 PMC: 10539269. DOI: 10.1007/s11302-022-09873-3.

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