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. 2009 Mar;5(1):51-61.
doi: 10.1007/s11302-008-9105-3. Epub 2008 Jul 10.

Allosteric modulation of adenosine receptors

Anikó Göblyös  1 , Ad P Ijzerman
Affiliations

Allosteric modulation of adenosine receptors

Anikó Göblyös et al. Purinergic Signal. 2009 Mar.

Abstract

Allosteric modulators for adenosine receptors may have potential therapeutic advantage over orthosteric ligands. Allosteric enhancers at the adenosine A(1) receptor have been linked to antiarrhythmic and antilipolytic activity. They may also have therapeutic potential as analgesics and neuroprotective agents. A(3) allosteric enhancers are postulated to be useful against ischemic conditions or as antitumor agents. In this review, we address recent developments regarding the medicinal chemistry of such compounds. Most efforts have been and are directed toward adenosine A(1) and A(3) receptors, whereas limited or no information is available for A(2A) and A(2B) receptors. We also discuss some findings, mostly receptor mutation studies, regarding localization of the allosteric binding sites on the receptors.

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Figures

Fig. 1
Fig. 1
Binding of an allosteric ligand (1) modulates the binding of hormone or neurotransmitter (2)
Fig. 2
Fig. 2
Allosteric modulators may either increase or decrease the effect of an agonist or an antagonist. An allosteric enhancer can be a more physiologic alternative to synthetic agonists (b, c). An allosteric enhancer can only act in the presence of an (endogenous) agonist. It mimics the duration and intensity of action of a hormone or neurotransmitter (a) much better than a synthetic agonist does (c). This combined action of two compounds (i.e., agonist and enhancer) might also induce selectivity of drug action
Fig. 3
Fig. 3
2-Amino-3-substituted thiophene derivatives, allosteric modulators for A1 adenosine receptors
Fig. 4
Fig. 4
2-Aminothiazoles and [1,2,4]thiadiazole analogues, questionable allosteric modulators for A1 adenosine receptors
Fig. 5
Fig. 5
Amiloride derivatives, allosteric modulators of adenosine receptors
Fig. 6
Fig. 6
Structures of allosteric modulators of A3 receptors
Fig. 7
Fig. 7
The location of amino acid residues involved in allosteric modulation of A1, A2A, and A3 receptors as displayed in a receptor homology model of the adenosine receptor (side and top view) based on the structure of the β2-adrenergic receptor cocrystallized with its ligand carazolol (PDB coordinates: 2rh1). C-α atoms at these locations are shown as spheres. The position of D55 in the A1 receptor is equivalent to D58 in the A3 receptor
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