Our laboratory has been one of the most active sources of new AR ligands that have therapeutic potential, and we are careful to cover promising discoveries with patent applications to safeguard the interest of public health and to facilitate translational medicine. Furthermore, we have designed and synthesized many ligands that are used widely in research. Synthetic selective ligands that either mimic the action of adenosine (i.e. agonists) in a fashion specific at a single subtype, or suppress it (i.e. antagonists), can be applied with great benefit in models of disease states, and therefore such agents are being explored as potential pharmaceuticals. For example, in the brain area for movement control (striatum), natural adenosine acting at postsynaptic A2A receptors generally suppresses movement. In Parkinsons Disease, one would like to achieve the blockade of this receptor to boost the dopaminergic signaling. This approach of using a selective AR antagonist to benefit patients suffering from a neurodegenerative disease is currently the focus of clinical trials. On the other hand, AR agonists are more applicable to disease treatment, e.g. in inflammatory diseases and cardioprotection. Thus, we are constantly on the lookout for the most viable disease targets and translational opportunities for our technology. Our collaborations include studies of the role of ARs in the central nervous system, inflammatory/immune system, cardiovascular system, skeletal muscle, and other systems. A structural understanding of the molecular recognition and activation of the ARs is an important component of our studies that leads to novel ligands. The introduction of novel compounds for disease applications is the culmination of a long process of molecular design. The more that is known about the 3-dimensional structure of the target receptor, the easier it is to design appropriate ligands. In that regard, we have made significant advances in the approaches to structure-based discovery of small molecular ligands of ARs. This will allow future research to design more effective agonists of the ARs in principle with fewer side effects due to high specificity for a particular receptor subtype. The rational design of AR ligands was greatly advanced by the recent elucidation of both the agonist-bound (activated) and antagonist-bound (inactive) states of the A2AAR. We have collaborated with one of the premier centers for X-ray crystallography of membrane-bound proteins, i.e. the lab of Prof. Ray Stevens of the Scripps Research Inst., to report the first X-ray structure of an agonist-bound A2AAR. We are now using this structure advantageously for in silico screening to discover new chemically diverse ligands and to modify existing ligands in ways made possible only through a detailed understanding of molecular recognition and activation of the receptor. This computerized process to discover new potential pharmaceuticals still requires chemical synthesis of target compounds to validate the structural hypotheses. This synthesis is carried out both in our lab and through collaborations. Our novel selective A3AR agonists and antagonists containing a methanocarba (bicyclo3.1.0hexane) ribose-ring substitution constrained in the receptor-preferred North (N) conformation have improved pharmacological profiles. Also, at the A1AR, (N)-methanocarba nucleosides were truncated to eliminate 5′-CH2OH with partial or full retention of agonism. Truncated derivatives have more drug-like physical properties;this approach is appealing for preclinical development of nucleoside analogues. Our ongoing program to develop selective A3AR agonists has resulted in advanced clinical trials of two nucleosides. Therapeutic interests related to selective ligands for the A3AR are anti-inflammatory, anti-ischemic (e.g. in the heart, brain, lungs, and skeletal muscle) and anticancer, by molecular mechanisms that entail modulation of the Wnt and the NF-κB signal transduction pathways. The A3AR is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A3AR as a potential therapeutic target. Currently, A3AR agonists discovered in our lab (IB-MECA and Cl-IB-MECA) are developed for the treatment of inflammatory diseases including rheumatoid arthritis and psoriasis;dry eye syndrome;and liver diseases such as hepatocellular carcinoma. Oral administration of IB-MECA for 12 weeks to patients with moderate-to-severe dry eye syndrome resulted in a statistically significant improvement in the mean change in clinical indicators, such as corneal staining, from baseline at week 12 in the treated group compared to placebo. A2BAR blockade inhibits growth of prostate cancer cells, suggesting selective A2BAR antagonists as potential novel therapeutics. Sterically constrained ((N )-methanocarba) adenosine derivatives were nanomolar full agonists of the A3AR and highly selective. Combined 2-arylethynyl-N6 -3-chlorobenzyl substitutions preserved A3AR affinity/ (e.g., 3,4-difluorophenylethynyl full agonist MRS5698). Receptor docking identified a large, mainly hydrophobic arylethynyl binding region and a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A2AAR is useful in guiding the design of new A3AR agonists. In collaboration with Daniela Salvemini, we have shown encouraging protective activity of A3AR agonists in models of chronic neuropathic pain. A3AR agonists suppress or prevent the development of chronic neuropathic pain in mice following chronic constriction injury or administration of cancer chemotherapeutic agents. Agents tested include widely used drugs in the taxane, platinum-complex and proteasome-inhibitor classes. These effects were naloxone insensitive and thus were not opioid receptor mediated. IB-MECA was more potent and efficacious than morphine. In addition, IB-MECA was equally as efficacious as gabapentin or amitriptyline, but more potent. Besides its potent standalone ability to reverse established mechanoallodynia, IB-MECA significantly increased the antiallodynic effects of all 3 analgesics. If used therapeutically, this could facilitate the life-saving use of cancer chemotherapy, which often has to be limited or discontinued because of severe side effects such as pain. Another promising application of AR ligands is the use of A3AR antagonists for topical application in the treatment of glaucoma. Certain A3AR antagonists from our lab and arising from outside collaborations are licensed for development as antiglaucoma agents. We have discovered positive allosteric modulators (PAMs) of the A3AR such as imidazoquinolinamine LUF6000 to modulate the actions of endogenous adenosine, potentially with fewer side effects than directly acting orthosteric agonists (with A. IJzerman). A related PAM was highly cardioprotective in an ischemia model. The objective was to magnify the beneficial effects of the endogenous adenosine released during stress conditions. These effects of the PAMs would be event-specific within the body, i.e. the PAM would have no biological effect on its own unless adenosine were locally elevated. A1 agonists that act selectively in the brain have long been sought as cerebroprotective and anticonvulsant agents. Most known A1 receptor agonists display unacceptable side effects due to their peripheral action, such as alteration of heart rate and blood pressure. We have recently discovered, using a rational design process based on computer modeling, one such drug-like compound, i.e. having the proper physicochemical properties to act at the desired site in the body, that seems to accomplish this goal. This compound MRS5474 is now under study by NINDS as a possible new antiepileptic agent.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Eddy, Matthew T; Gao, Zhan-Guo; Mannes, Philip et al. (2018) Extrinsic Tryptophans as NMR Probes of Allosteric Coupling in Membrane Proteins: Application to the A2A Adenosine Receptor. J Am Chem Soc 140:8228-8235
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
Xia, Lizi; Kyrizaki, Athina; Tosh, Dilip K et al. (2018) A binding kinetics study of human adenosine A3 receptor agonists. Biochem Pharmacol 153:248-259
Tosh, Dilip K; Ciancetta, Antonella; Mannes, Philip et al. (2018) Repurposing of a Nucleoside Scaffold from Adenosine Receptor Agonists to Opioid Receptor Antagonists. ACS Omega 3:12658-12678
Taura, Jaume; Nolen, Ernest G; Cabré, Gisela et al. (2018) Remote control of movement disorders using a photoactive adenosine A2A receptor antagonist. J Control Release 283:135-142
Carlin, Jesse Lea; Jain, Shalini; Duroux, Romain et al. (2018) Activation of adenosine A2A or A2B receptors causes hypothermia in mice. Neuropharmacology 139:268-278
Jacobson, Kenneth A; Merighi, Stefania; Varani, Katia et al. (2018) A3 Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy. Med Res Rev 38:1031-1072
Eddy, Matthew T; Lee, Ming-Yue; Gao, Zhan-Guo et al. (2018) Allosteric Coupling of Drug Binding and Intracellular Signaling in the A2A Adenosine Receptor. Cell 172:68-80.e12
Gao, Zhan-Guo; Inoue, Asuka; Jacobson, Kenneth A (2018) On the G protein-coupling selectivity of the native A2B adenosine receptor. Biochem Pharmacol 151:201-213
White, Kate L; Eddy, Matthew T; Gao, Zhan-Guo et al. (2018) Structural Connection between Activation Microswitch and Allosteric Sodium Site in GPCR Signaling. Structure 26:259-269.e5

Showing the most recent 10 out of 119 publications