A3 Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

Abstract

The A₃ adenosine receptor (A₃ AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A₃ AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen-activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A₃ AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A₃ AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure-activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug-like characteristics. The efficacy of nucleoside agonists may be suppressed to produce antagonists, by structural modification of the ribose moiety. Diverse classes of heterocycles have been discovered as selective A₃ AR blockers, although with large species differences. Thus, as a result of intense basic research efforts, the outlook for development of A₃ AR modulators for human therapeutics is encouraging. Two prototypical selective agonists, N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA; CF101) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; CF102), have progressed to advanced clinical trials. They were found safe and well tolerated in all preclinical and human clinical studies and showed promising results, particularly in psoriasis and RA, where the A₃ AR is both a promising therapeutic target and a biologically predictive marker, suggesting a personalized medicine approach. Targeting the A₃ AR may pave the way for safe and efficacious treatments for patient populations affected by inflammatory diseases, cancer, and other conditions.

Keywords: A3 adenosine receptor; cancer; drug development; inflammation; therapy.

FIGURE 1

Structures of adenosine or 1,3-dialkylxanthine riboside derivatives that act as agonists of the A₃AR. Compound 16 (CGS21680, not shown) is an A_2AAR agonist

FIGURE 2

Structures of (N)-methanocarba-adenosine derivatives that act as agonists of the A₃AR

FIGURE 3

Structures of (N)-methanocarba and riboside derivatives of adenosine or 1,3-dialkylxanthine that act as partial agonists or antagonists of the A₃AR

FIGURE 4

Monocycle-based A₃AR antagonists

FIGURE 5

Bicycle-based A₃AR antagonists

FIGURE 6

Tricycle-based A₃AR antagonists

FIGURE 7

Tricycle-based A₃AR antagonists

FIGURE 8

Allosteric modulators of the A₃AR

FIGURE 9

(A) Docking pose of 3,4-difluorophenyl agonist analogue MRS5980 (27) at the hA₃AR homology model, in which TM2 is based on its position in the active β² adrenergic receptor. Residues interacting with the ligand (magenta carbon atoms) are labeled. H-bond and π–π interactions are represented as green solid and cyan dashed lines, respectively. Nonconserved ARs residues are in italics. (B) Docking pose of biphenyl agonist analogue MRS5679 (26) at the hA₃AR homology model. Residues interacting with the ligand (violet carbon atoms) are labeled and H-bond interactions are represented as green solid lines. The degree of displacement of TM2 with respect to the TM bundle in hA₃AR homology models based on the hA_2AAR (red ribbon), hybrid hA_2AAR-β₂ adrenergic receptor (purple ribbon), and hybrid hA_2AAR-opsin (violet ribbon) templates is highlighted with an arrow. TM1 is omitted to aid visualization

FIGURE 10

Intracellular pathways of A₃AR in immune and cancer cells. Schematic diagram showing the main signaling pathways triggered by adenosine through A₃AR activation in different cellular types. A₃AR preferentially couples to Gi. PLC activation, and even the Ca²⁺ effects observed at high concentrations of A₃AR agonists, could conceivably be triggered by mechanisms other than Gq, such as Gβγ subunits