Conclusion - The picture that has emerged over the last several years suggests that the therapeutic potential of B1 antagonists to treat pain is broader than initially envisaged and could now include certain types of acute pain and neuropathic pain, in addition to chronic inflammatory pain. As such, B1 antagonists exhibit an analgesic profile that overlaps significantly with the opiates, but are unlikely to exhibit the unwanted side effects of morphine-like drugs such as sedation, respiratory depression and abuse potential. In addition, targeting both peripheral and central (e.g. spinal cord) sites of action may be important for optimizing the efficacy of this novel class of compounds.


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Chapter 13. A3 Adenosine Receptors

Kenneth A. Jacobson, Susanna Tchilibon, Bhalchandra V. Joshi and Zhan-Guo Gao

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD 20892

Introduction - Extracellular adenosine (1) is involved in many cytoprotective functions of the body, including conditioning the heart against ischemia, counteracting the damaging effects of excitotoxicity and seizure activity in the brain, and suppressing an excessive immune and inflammatory response (1). The possibilities of therapeutic intervention based on modulation of adenosine receptors and adenosine levels are numerous. There are four subtypes of adenosine receptors; of which the A3 receptor was most recently identified as a result of its cloning from various species (2). The A3 receptor is activated endogenously by higher concentrations of adenosine than are required for activation of the A1 /A2a receptors. The effector mechanisms are inhibition of adenylate cyclase and stimulation of phospholipase C (1,3). Both protective (usually at nM concentrations) and damaging effects (usually at pM concentrations) of A3 agonists have been studied (3). The receptor is distributed at low, diffuse levels in the brain and in the human periphery where it is present in lungs, liver, heart, and immune cells such as eosinophils (2). Therapeutic interests related to A3 receptors are: antiinflammatory (possibly through depression of TNF-a levels) (4), cardioprotective (5), cerebroprotective (6), anticancer (7), and antiglaucoma (8). A mouse line lacking the A3 receptor demonstrated that this is a non-lethal mutation that has inflammatory, cardiovascular, and behavioral consequences (9-11). The A3-modulated release of histamine from mast cells may be specific to rodent species (12).


Mutagenesis was recently carried out on the human A3 receptor, a 7TM receptor, to locate a putative ligand binding site (13). In some cases, different amino acid residues are associated with agonist or with antagonist binding. Movement of a conserved Trp in TM6 has been proposed as an important step in receptor activation. In a rhodopsin-based docking model of the human A3 receptor, this residue rotates characteristically upon in silico binding of agonists but not antagonists. This may be linked to a required rotation of TM6 during the receptor activation process (13).

Allosteric Modulators - Pyridinylisoquinolines (VUF5455, 2) and imidazoquinolines (DU124183, 3) were shown to positively modulate A3 binding and/or action of agonists, although both substances retain antagonistic properties as well (14,15). These derivatives had no effects at the A1/ A2a receptor subtypes. Compound 3 augmented

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