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 an don the possibility of therapeutics for treating neurodegenerative diseases. Chronic treatment with an adenosine agonist improves spaital 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. 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, ether at the level of receptor or second messenger. An A3 agonist proved to be highly cerebroprotective in an ischemic model in gerbils. 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 receptor protein, based on sequence analyses and computerized energy minimizations. A hypothesis concerning the mode of binding to ligands to adenosine receptors has been derived. This hypothesis is consistent with pharmacological observations and site directed mutagenesis experiments, in which key histidyl residues have been replaced by other amino acids.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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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