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A3 Adenosine Receptor Agonists: History and Future Perspectives

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Book cover A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics

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Abstract

IB-MECA, the first selective A3 adenosine receptor (A3AR) agonist, was reported in 1993, and since then numerous adenosine derivatives have been modified to optimize their interaction with the A3AR. IB-MECA (CF101) and its 2-chloro analogue, Cl-IB-MECA (CF102) are in Phase II clinical trials for treatment of autoimmune inflammatory diseases and cancer, respectively. Additional structural modifications made at the N 6 and 2 positions and in the ribose moiety of adenosine derivatives have led to even more potent and selective A3AR agonists. A newer generation of A3AR agonists incorporates the (N)-methanocarba ring system in place of the ribose moiety, leading to increased affinity and subtype selectivity. The affinity of certain nucleoside derivatives at the A3AR has been found to be species-dependent. Combinations of efficacy-lowering substitutions can convert agonists into partial agonists and even A3AR antagonists. In general, A3 agonists have a cytoprotective effect, for example in the heart, brain, and skeletal muscle. Contradictory (or opposite) pharmacological effects of A3AR agonists have also been noted, depending on the dose and system, which has led to a proposed concept of “effect reversal” for this receptor. The potency and efficacy of various adenosine derivatives at the A3AR also depends on the second messenger system being studied. Differential effects of A3AR agonists in the inhibition of adenylate cyclase, stimulation of [35S]GTPγS binding, and translocation of arrestin, and other effector systems may be compared. The potency and or efficacy of A3AR agonists may also be enhanced by allosteric modulators. Several heterocyclic classes of positive allosteric modulators of the A3AR, including 1H-imidazo-[4,5-c]quinolines such as LUF6000 (N-(3,4-dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-amine) and pyridinylisoquinolines, have been reported. Structure activity relationships (SARs) of both agonists and allosteric enhancers are covered in detail in this chapter.

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Abbreviations

AR:

Adenosine receptor

cAMP:

Adenosine 3′,5′-cyclic phosphate

CHO:

Chinese hamster ovary

Cl-IB-MECA:

2-Chloro-N 6-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine

DBXRM:

7-β-D-Ribofuronamide

DU124183:

2-Cyclopentyl-4-phenylamino-1H-imidazo[4,5-c]quinoline

GPCR:

G protein-coupled receptor

h:

Human

HEK293 cells:

Human embryonic kidney 293 cells

I-AB-MECA:

N 6-(4-Amino-3-iodobenzyl)-5′-N-methylcabroxamidoadenosine

IB-MECA:

N 6-(3-Iodobenzyl)-5′-N-methylcarboxamidoadenosine

LJ-529:

2-Chloro-N 6-(3-iodobenzyl)-4′-thioadenosine-5′-methyluronamide

LJ-1251:

(2R,3R,4S)-2-(2-Chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol

LJ-1416:

(2R,3R,4S)-2-(2-Chloro-6-(3-chlorobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol

LUF6000:

N-(3,4-Dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-amine

Me:

Methyl

MRS1292:

(2R,3R,4S,5S)-2-[N 6-3-Iodobenzyl)adenos-9’-yl]-7-aza-1-oxa-6-oxospiro[4.4]-nonan-4,5-diol

MRS3558:

((1’R,2’R,3’S,4’R,5’S)-4-{2-Chloro-6-[(3-iodophenylmethyl)amino]purin-9-yl}-1-(methylaminocarbonyl)bicyclo-[3.1.0]-hexane-2,3-diol)

MRS5127:

(1′R,2′R,3′S,4′R,5′S)-4′-[2-Chloro-6-(3-iodobenzylamino)-purine]-2′,3′-O-dihydroxybicyclo-[3.1.0]hexane

MRS5147:

(1′R,2′R,3′S,4′R,5′S)-4′-[2-Chloro-6-(3-bromobenzylamino)-purine]-2′,3′-O-dihydroxybicyclo-[3.1.0]hexane

MRS5151:

(1′S,2′R,3′S,4′S,5′S)-4′-[6-(3-Chlorobenzylamino)-2-(5-hydroxycarbonyl-1-pentynyl)-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]hexane-1′-carboxylic acid N-methylamide

NECA:

Adenosine 5′-N-ethyluronamide

QSAR:

Quantitative structure–activity relationships

r:

Rat

SARs:

Structure–activity relationships

VUF5455:

4-Methoxy-N-[7-methyl-3-(2-pyridinyl)-1-isoquinolinyl]benzamide

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Acknowledgements

This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

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Authors and Affiliations

  1. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-0810, USA

    Kenneth A. Jacobson

  2. Molecular Recognition Section, Bldg. 8A, NIH, NIDDK, LBC, Bethesda, MD, 20892-0810, USA

    Kenneth A. Jacobson

  3. Bldg. 8A, NIH, NIDDK, LBC, Bethesda, MD, 20892-0810, USA

    Zhan-Guo Gao, Dilip K. Tosh, Gangadhar J. Sanjayan & Sonia de Castro

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Correspondence to Kenneth A. Jacobson .

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Jacobson, K.A., Gao, ZG., Tosh, D.K., Sanjayan, G.J., de Castro, S. (2010). A3 Adenosine Receptor Agonists: History and Future Perspectives. In: Borea, P. (eds) A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3144-0_6

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