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

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 A(2A)AR 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.

Fig. 1

a Nonselective AR and A₁AR selective agonists (including nucleosides and a nonnucleoside derivative 15). b A_2AAR, A_2BAR, and A₃AR selective agonists (including nucleosides and a nonnucleoside derivative 21). AR affinites (Table 1) and selectivities of many of these ligands are available [1, 55]

Fig. 2

a. Nonselective AR antagonists and A₁AR and A_2AAR selective antagonists (including xanthines and nonxanthine derivatives 44–51). b A_2BAR (xanthines 52–59) and A₃AR selective (nonxanthine derivatives 60–69) antagonists. Compound 68 is a truncated nucleoside derivative that displays A₃AR antagonist properties. AR affinites (Table 1) and selectivities of many of these ligands are available [1, 42, 55]

Fig. 3

a Nonselective and selective P2YR agonists and related substances (including nucleotide derivatives). b Nonselective and selective P2YR antagonists (including nucleotide and nucleotide derivatives). Note that NF546 104 is a P2Y₁₁R agonist, although it belongs to a structural class of antagonists. Compound 110 is a P2Y₁R antagonist containing a novel chemotype, and 111–115 are P2Y₁₂R antagonists. Compound 116 is a P2Y₁₄R antagonist containing a novel chemotype. P2Y potencies of many of these ligands are available in Table 1 or reference [2]