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Xanthine is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, theophylline, and theobromine.
Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building blocks of RNA (and its derivative deoxyadenosine is a building block of DNA), which are essential for all life on earth. Its derivatives include the energy carriers adenosine mono-, di-, and triphosphate, also known as AMP/ADP/ATP. Cyclic adenosine monophosphate (cAMP) is pervasive in signal transduction. Adenosine is used as an intravenous medication for some cardiac arrhythmias.
The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different gene.
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ligare, which means 'to bind'. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure.
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Paraxanthine, also known as 1,7-dimethylxanthine, is a metabolite of theophylline and theobromine, two well-known stimulants found in coffee, tea, and chocolate. It is a member of the xanthine family of alkaloids, which includes theophylline, theobromine and caffeine.
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8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, PD-116,948) is a drug which acts as a potent and selective antagonist for the adenosine A1 receptor. It has high selectivity for A1 over other adenosine receptor subtypes, but as with other xanthine derivatives DPCPX also acts as a phosphodiesterase inhibitor, and is almost as potent as rolipram at inhibiting PDE4. It has been used to study the function of the adenosine A1 receptor in animals, which has been found to be involved in several important functions such as regulation of breathing and activity in various regions of the brain, and DPCPX has also been shown to produce behavioural effects such as increasing the hallucinogen-appropriate responding produced by the 5-HT2A agonist DOI, and the dopamine release induced by MDMA, as well as having interactions with a range of anticonvulsant drugs.
KF-26777 is a drug which acts as a potent and selective antagonist for the adenosine A3 receptor, with sub-nanomolar affinity (A3 Ki=0.2nM) and high selectivity over the other three adenosine receptor subtypes. Simple xanthine derivatives such as caffeine and DPCPX have generally low affinity for the A3 subtype and must be extended by expanding the ring system and adding an aromatic group to give high A3 affinity and selectivity.
PSB-10 is a drug which acts as a selective antagonist for the adenosine A3 receptor (ki value at human A3 receptor is 0.44 nM), with high selectivity over the other three adenosine receptor subtypes (ki values at human A1, A2A and A2B receptors are 4.1, 3.3 and 30 μM). Further pharmacological experiments in a [35S]GTPγS binding assay using hA3-CHO-cells indicated that PSB-10 acts as an inverse agonist (IC50 = 4 nM). It has been shown to produce antiinflammatory effects in animal studies. Simple xanthine derivatives such as caffeine and DPCPX have generally low affinity for the A3 subtype and must be extended by expanding the ring system and adding an aromatic group to give high A3 affinity and selectivity. The affinity towards adenosine A3 subtype was measured against the radioligand PSB-11.
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Mitragynine pseudoindoxyl is a rearrangement product of 7-hydroxymitragynine and active metabolite of mitragynine. It is an analgesic being more potent than morphine.
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Adenosine A2A receptor antagonists are a class of drugs that blocks adenosine at the adenosine A2A receptor. Notable adenosine A2A receptor antagonists include caffeine, theophylline and istradefylline.
HS665 is a drug which acts as a potent and selective κ-opioid receptor agonist, and has analgesic effects in animal studies. HS665 is not an agonist for the mu receptor, leading to less potential for abuse.
ISAM-140 is a selective non-xanthinic adenosine A2B receptor atagonist. Discovered in 2016, has a Ki of 3.49 nM in A2B receptor and >1000-fold selectivity with respect to the other three adenosine receptor subtypes. It has been shown to help immune system to attack cancer cells in in vitro assays, by rescuing T and NK cell proliferation, cytokine release and TIL infiltration.
References
- ↑ Müller, CE; Jacobson, KA (2011). Xanthines as adenosine receptor antagonists. Handbook of Experimental Pharmacology. Vol. 200. pp. 151–99. doi:10.1007/978-3-642-13443-2_6. ISBN 978-3-642-13442-5. PMC 3882893 . PMID 20859796.
- ↑ Rivera-Oliver, Marla; Díaz-Ríos, Manuel (April 2014). "Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: A review". Life Sciences. 101 (1–2): 1–9. doi:10.1016/j.lfs.2014.01.083. PMC 4115368 . PMID 24530739.
- ↑ Hauber, W.; Muenkle, M. (July 1996). "The adenosine receptor antagonist theophylline induces a monoamine-dependent increase of the anticataleptic effects of NMDA receptor antagonists". Naunyn-Schmiedeberg's Archives of Pharmacology. 354 (2): 179–186. doi:10.1007/BF00178718. PMID 8857595. S2CID 21765941.
- ↑ Jiang, Jie; Seel, Catharina Julia; Temirak, Ahmed; Namasivayam, Vigneshwaran; Arridu, Antonella; Schabikowski, Jakub; Baqi, Younis; Hinz, Sonja; Hockemeyer, Jörg; Müller, Christa E. (2019-04-25). "A2B Adenosine Receptor Antagonists with Picomolar Potency". Journal of Medicinal Chemistry. 62 (8): 4032–4055. doi:10.1021/acs.jmedchem.9b00071. ISSN 1520-4804. PMID 30835463. S2CID 73472174.
- ↑ El Maatougui, Abdelaziz; Azuaje, Jhonny; González-Gómez, Manuel; Miguez, Gabriel; Crespo, Abel; Carbajales, Carlos; Escalante, Luz; García-Mera, Xerardo; Gutiérrez-de-Terán, Hugo; Sotelo, Eddy (2016-03-10). "Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes". Journal of Medicinal Chemistry. 59 (5): 1967–1983. doi:10.1021/acs.jmedchem.5b01586. ISSN 1520-4804. PMID 26824742.
- ↑ Prieto-Díaz, Rubén; González-Gómez, Manuel; Fojo-Carballo, Hugo; Azuaje, Jhonny; El Maatougui, Abdelaziz; Majellaro, Maria; Loza, María I.; Brea, José; Fernández-Dueñas, Víctor; Paleo, M. Rita; Díaz-Holguín, Alejandro; Garcia-Pinel, Beatriz; Mallo-Abreu, Ana; Estévez, Juan C.; Andújar-Arias, Antonio (2022-12-14). "Exploring the Effect of Halogenation in a Series of Potent and Selective A 2B Adenosine Receptor Antagonists". Journal of Medicinal Chemistry. 66 (1): 890–912. doi:10.1021/acs.jmedchem.2c01768. ISSN 0022-2623. PMC 9841532 . PMID 36517209. S2CID 254759241.
- ↑ Borodovsky, Alexandra; Barbon, Christine M.; Wang, Yanjun; Ye, Minwei; Prickett, Laura; Chandra, Dinesh; Shaw, Joseph; Deng, Nanhua; Sachsenmeier, Kris; Clarke, James D.; Linghu, Bolan; Brown, Giles A.; Brown, James; Congreve, Miles; Cheng, Robert Ky (July 2020). "Small molecule AZD4635 inhibitor of A2AR signaling rescues immune cell function including CD103+ dendritic cells enhancing anti-tumor immunity". Journal for Immunotherapy of Cancer. 8 (2): e000417. doi:10.1136/jitc-2019-000417. ISSN 2051-1426. PMC 7394305 . PMID 32727810.
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