Products Cited in Publications Worldwide Discovery of Allosteric Modulators of the A3 Adenosine Receptor for Treatment of Chronic Diseases

Discovery of Allosteric Modulators of the A3 Adenosine Receptor for Treatment of Chronic Diseases

Fallot, Lucas Brett

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 µM) derivative increased the A3AR agonist potency two-fold in [ 35S]GTPγS binding, as well as Emax (242%). 2-(Heptan-4-yl)-N-(3,4-dichlorophenyl) 2, 2-(hept-4-en-1-yl)-N-(3,4- viii dichlorophenyl) 10, and 2-(heptan-4-yl)-N-(4-iodophenyl) 31 (1 µM) 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.

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Cyclohept-4-enecarboxylic acid

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