Discovery of Allosteric Modulators of the A3 Adenosine Receptor for Treatment of Chronic Diseases
Abstract
Positive allosteric modulators (PAMs) of G protein-coupled receptors (GPCRs) bind to topographically distinct sites from orthosteric agonists, causing receptor conformational changes that increase agonist affinity, potency, and/or efficacy. 1Himidazo[4,5-c]quinolin-4-amine derivatives were identified as A3 adenosine receptor (A3AR) PAMs. Here, we introduce a 6-step synthesis applied to four groups of 1Himidazo[4,5-c]quinolin-4-amine derivatives to explore structure-activity relationships and pharmacokinetics. We show the ability to fine-tune both 2-cycloalkyl and open ring derivatives as competitive antagonists and/or allosteric modulators. These activities were separated pharmacologically using chimeric mouse/human A3ARs to show the PAM binding region likely to occur at a hydrophobic site on the A3AR cytosolic interface distinct from the orthosteric site. 2-Cyclononyl-N-(3,4-dichlorophenyl) 20 (1 micro M) derivative increased the A3AR agonist potency two-fold in [35S]GTPgammaS binding, as well as Emax (242%). 2-(Heptan-4-yl)-N-(3,4-dichlorophenyl) 2, 2-(hept-4-en-1-yl)-N-(3,4-dichlorophenyl) 10, and 2-(heptan-4-yl)-N-(4-iodophenyl) 31 (1 micro M) derivatives were highly efficacious (Emax = 216%, 241% and, 223%, respectively). Although hydrophobic and having low permeability and high plasma protein binding, derivative 10 was orally bioavailable in the rat. The derivatives tested lacked high-affinity off-target binding to forty-five other membrane proteins. Furthermore, we demonstrated a route for radioiodination at the para-position of a 4-phenylamino substituent to prepare a radioligand for allosteric site binding. Herein, we advanced the allosteric approach to developing drugs for A3AR activation that are potentially event- and site-specific in action.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 23, 2022
- Accession Number
- AD1212219
Entities
People
- Lucas B. Fallot
Organizations
- Uniformed Services University of the Health Sciences