The extracellular adenosine receptor has a modulatory role in the nervous, circulatory, endocrine and immunological systems. The prospect of harnessing these effects specifically for therapeutic purposes is attractive. Recently this project has focused on the effects of adenosine agonists and antagonists in the central nervous system and on the possibility of therapeutics for treating neurodegenerative diseases. Chronic treatment with an adenosine agonist improves spatial memory retention and acquisition and indicates necessity of further studies directed towards Alzheimer's disease. Neuroprotective effects of acutely administered A1 receptor agonists and chronically administered A1 receptor antagonists have been demonstrated in a model of global ischemia in gerbils. Adenosine agonists prevent convulsions in several chemical and electrical seizure models and protect against excitotoxic neurodegeneration agonists and antagonists suggests some adaptation (sensitization by antagonists/desensitization by agonists) of the mechanism of receptor activation, either at the level of receptor or second messenger. We have synthesized the first selective A3 receptor agonists and antagonists. An A3 agonist, administered chronically, proved to be highly cerebro-protective in an ischemic model in gerbils. A3 agonists cause morpholigical and biochemical changes in astroglial cells. An acutely administered A3 agonist, Cl-IB-MECA, was cardioprotective in cell culture, through the selective activation of A3 receptors. The protection was blocked in the presence of a selective A3 receptor antagonist. In summary, highly selective adenosine analogues may have therapeutic potential in treatment of cerebral ischemia/stroke and possibly other neurodegenerative disorders as well. Since the three major subtypes of adenosine receptors have been cloned it has been possible to conduct molecular modeling of the redeptor protein, based on sequence analyses and computerized energy minimizations. We have found that A3 receptors occur in high density on human peripheral blood eosinophils. Activation of these receptors raises levels of intracellular calcium. It is proposed that modulation of A3 receptors may be useful in treating asthma and inflammatory diseases. The pharmacolgical properties of selective A3 antagonists developed in our lab are being explored. A link between A3 receptors and programmed cell death has been discovered.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Intramural Research (Z01)
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Wahlman, Carrie; Doyle, Timothy M; Little, Joshua W et al. (2018) Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. Pain 159:1025-1034
Jacobson, Kenneth A; Gao, Zhan-Guo; Paoletta, Silvia et al. (2015) John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors. Comput Struct Biotechnol J 13:286-98
Tosh, Dilip K; Padia, Janak; Salvemini, Daniela et al. (2015) Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain. Purinergic Signal 11:371-87
Jacobson, Kenneth A (2015) New paradigms in GPCR drug discovery. Biochem Pharmacol 98:541-55
Kiesewetter, Dale O; Lang, Lixin; Ma, Ying et al. (2009) Synthesis and characterization of [76Br]-labeled high-affinity A3 adenosine receptor ligands for positron emission tomography. Nucl Med Biol 36:3-10
Pal, Shantanu; Choi, Won Jun; Choe, Seung Ah et al. (2009) Structure-activity relationships of truncated adenosine derivatives as highly potent and selective human A3 adenosine receptor antagonists. Bioorg Med Chem 17:3733-8
Tosh, Dilip K; Chinn, Moshe; Ivanov, Andrei A et al. (2009) Functionalized congeners of A3 adenosine receptor-selective nucleosides containing a bicyclo[3.1.0]hexane ring system. J Med Chem 52:7580-92
Jacobson, Kenneth A; Zablocki, Jeff; Bhagwat, Shripad (2009) Preface: special issue on medicinal chemistry of purines. Purinergic Signal 5:1
Ivanov, Andrei A; Jacobson, Kenneth A (2008) Molecular modeling of a PAMAM-CGS21680 dendrimer bound to an A2A adenosine receptor homodimer. Bioorg Med Chem Lett 18:4312-5
Choi, Won Jun; Lee, Hyuk Woo; Hou, Xiyan et al. (2008) Synthesis of 2-chloro-N6-substituted-4'-thioadenosine-5'-N, N-dialkyluronamides as potent and selective A3 adenosine receptor antagonists. Nucleic Acids Symp Ser (Oxf) :645-6

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