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. We have developed research tools for the characterization of adenosine receptors in vitro and in vivo. We have synthesized new drug analogues and elucidated structure activity relationships at receptor subtypes. Derivatives of adenosine with chemical modifications at the N6 and C-2 positions of the purine ring act as selective adenosine agonists. A1- agonists are being explored as cerbroprotective agents. To enhance brain uptake, prodrug schemes are being examined. APEC, an A2-selective adenosine amine cogener served as the basis for a photoaffinity labeling reagent that allowed the first determination of the molecular weight of the receptor. Functionalized cogeners of xanthines act as potent adenosine antagonists and are being developed as radioactive tracers for adenosine receptors and as affinity labels. Tritiated XAC (xanthine amine cogener) was used to characterize the human striatal A2 adenosine receptor. Since the two 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. The hypothesis concerning the mode of binding of 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with pharmacological observations and site directed mutagenesis experiments, in which key histidyl residues have been replaced by other amino acids.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
5
Fiscal Year
1992
Total Cost
Indirect Cost
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State
Country
United States
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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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