98408-17-4Relevant articles and documents
Discovery of Tricyclic Xanthines as Agonists of the Cannabinoid-Activated Orphan G-Protein-Coupled Receptor GPR18
Schoeder, Clara T.,Mahardhika, Andhika B.,Drabczyńska, Anna,Kie?-Kononowicz, Katarzyna,Müller, Christa E.
, p. 2024 - 2031 (2020/07/03)
GPR18 is a rhodopsin-like orphan G-protein-coupled receptor (GPCR) that is activated by the natural cannabinoid (CB) Δ9-tetrahydrocannabinol (THC). It is highly expressed in immune cells and represents a promising new drug target. However, THC is much more potent in activating CB receptors than GPR18, and several other proposed lipidic agonists for GPR18 have not been independently confirmed. Herein we describe the first non-lipid-like agonists for GPR18 based on a tricyclic xanthine-derived scaffold, along with initial structure-activity relationships. PSB-KD107 (5) and PSB-KD477 (16) displayed significantly higher potency and efficacy than THC, determined in a GPR18-dependent β-arrestin recruitment assay, and were found to be selective versus the CB-sensitive receptors CB1, CB2, and GPR55. Structure-activity relationships were steep, and indole substitution was crucial for biological activity. These first selective agonists, which are structurally distinct from the lipidic agonist(s), will allow target validation studies and may eventually contribute to the deorphanization of GPR18.
Novel multi-target directed ligands based on annelated xanthine scaffold with aromatic substituents acting on adenosine receptor and monoamine oxidase B. Synthesis, in vitro and in silico studies
Za?uski, Micha?,Schabikowski, Jakub,Schlenk, Miriam,Olejarz-Maciej, Agnieszka,Kubas, Bart?omiej,Karcz, Tadeusz,Kuder, Kamil,Latacz, Gniewomir,Zygmunt, Ma?gorzata,Synak, David,Hinz, Sonja,Müller, Christa E.,Kie?-Kononowicz, Katarzyna
, p. 1195 - 1210 (2019/02/26)
N9-Benzyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones were designed as dual-target-directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blockade of monoamine oxidase B (MAO-B). A library of 37 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. A systematic modification of the tricyclic structures based on a xanthine core by enlargement of the third heterocyclic ring or attachment of various substituted benzyl moieties resulted in the development of 9-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (9u; Ki human A2AAR: 189 nM and IC50 human MAO-B: 570 nM) as the most potent dual acting ligand of the series displaying high selectivity versus related targets. Moreover, some potent, selective MAO-B inhibitors were identified in the group of pyrimido- and 1,3-diazepino[2,1-f]purinediones. Compound 10d (10-(3,4-dichlorobenzyl)-1,3-dimethyl-7,8,9,10-tetrahydro-1H-[1,3]diazepino[2,1-f]purine-2,4(3H,6H)-dione) displayed an IC50 value at human MAO-B of 83 nM. Analysis of structure–activity relationships was complemented by molecular docking studies based on previously published X-ray structures of the protein targets. An extended biological profile was determined for selected compounds including in vitro evaluation of potential hepatotoxicity calculated in silico and antioxidant properties as an additional desirable activity. The new molecules acting as dual target drugs may provide symptomatic relief as well as disease-modifying effects for neurodegenerative diseases, in particular Parkinson's disease.
ANTAGONISTS OF THE GOLGI REASSEMBLY-STACKING PROTEIN OF 55 KDA (GRASP55) AND USES THEREOF
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, (2017/02/28)
The present invention relates to new compounds useful as antagonists of the Golgi reassembly-stacking protein of 55 k Da (Grasp55), and in particular to their use as a non-hormonal male contraceptive. The present invention also relates to these compounds for use as a medicament, in particular for the treatment or the prevention of a disease selected from the group consisting of cancer, metastases and an inflammatory disease.
Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones
Drabczyńska, Anna,Yuzlenko, Olga,K?se, Meryem,Paskaleva, Minka,Schiedel, Anke C.,Karolak-Wojciechowska, Janina,Handzlik, Jadwiga,Karcz, Tadeusz,Kuder, Kamil,Müller, Christa E.,Kie?-Kononowicz, Katarzyna
scheme or table, p. 3590 - 3607 (2011/11/05)
Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3- dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1-33) were evaluated for their affinity to rat adenosine A1 and A2A receptors. Selected compounds were additionally investigated for affinity to the human A1, A2A, A2B and A 3 receptor subtypes. The results of the radioligand binding assays at adenosine A1 and A2A receptors showed that most of the compounds exhibited adenosine A2A receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A2A affinity. The most potent A2A ligands of the present series were compounds 6 (Ki 0.33 μM rat A2A, 0.31 μM human A2A), 8 (Ki 0.98 μM rat A2A, 0.42 μM human A2A) and 15 (Ki 0.24 μM rat A2A, 0.61 μM human A2A) with the latter one showing high A 2A selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A2A receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power (q2 = 0.88) for A2A AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure-activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A2A antagonists with good water-solubility.
Modes of xanthine complexation to dirhodium tetrakis[(R)-α-methoxy-α-(trifluoromethyl)-phenylacetate] in solution and in the solid state
Rockitt, Sven,Wartchow, Rudolf,Duddeck, Helmut,Drabczynska, Anna,Kiec-Kononowicz, Katarzyna
, p. 319 - 324 (2007/10/03)
It is shown by IR and NMR studies that the xanthines 1-5 prefer a side-on complexation to the chiral dirhodium tetrakis[(R)-α-methoxy-a-(trifluoromethyl)phenylacetate] (Rh*) in solution whereas carbonyl groups are involved in the solid state. For 6, at le
