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G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions

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Abstract

The medicinal chemistry and pharmacology of the four subtypes of adenosine receptors (ARs) and the eight subtypes of P2Y receptors (P2YRs, activated by a range of purine and pyrimidine mono- and dinucleotides) has recently advanced significantly leading to selective ligands. X-ray crystallographic structures of both agonist- and antagonist-bound forms of the A2AAR have provided unprecedented three-dimensional detail concerning molecular recognition in the binding site and the conformational changes in receptor activation. It is apparent that this ubiquitous cell signaling system has implications for understanding and treating many diseases. ATP and other nucleotides are readily released from intracellular sources under conditions of injury and organ stress, such as hypoxia, ischemia, or mechanical stress, and through channels and vesicular release. Adenosine may be generated extracellularly or by cellular release. Therefore, depending on pathophysiological factors, in a given tissue, there is often a tonic activation of one or more of the ARs or P2YRs that can be modulated by exogenous agents for a beneficial effect. Thus, this field has provided fertile ground for pharmaceutical development, leading to clinical trials of selective receptor ligands as imaging agents or for conditions including cardiac arrhythmias, ischemia/reperfusion injury, diabetes, pain, thrombosis, Parkinson’s disease, rheumatoid arthritis, psoriasis, dry eye disease, pulmonary diseases such as cystic fibrosis, glaucoma, cancer, chronic hepatitis C, and other diseases.

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Abbreviations

AR:

Adenosine receptor

EL:

Extracellular loop

GPCR:

G protein-coupled receptor

IL:

Intracellular loop

TM:

Transmembrane helix

NECA:

Adenosine-5′-N-ethyluronamide

PD:

Parkinson’s disease

PET:

Positron emission tomography

SAR:

Structure–activity relationship

SPECT:

Single photon emission tomography

UDPG:

Uridine-5′-diphosphoglucose

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Acknowledgements

Supported by the NIDDK Intramural Research Program, National Institutes of Health.

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Authors and Affiliations

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

    Kenneth A. Jacobson, Ramachandran Balasubramanian, Francesca Deflorian & Zhan-Guo Gao

  2. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD, 20892-0810, USA

    Kenneth A. Jacobson

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  1. Kenneth A. Jacobson
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  2. Ramachandran Balasubramanian
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  3. Francesca Deflorian
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Correspondence to Kenneth A. Jacobson.

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Jacobson, K.A., Balasubramanian, R., Deflorian, F. et al. G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions. Purinergic Signalling 8, 419–436 (2012). https://doi.org/10.1007/s11302-012-9294-7

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  • DOI: https://doi.org/10.1007/s11302-012-9294-7

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