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81.
Pier Giovanni Baraldi Mojgan Aghazadeh Tabrizi Francesca Fruttarolo Romeo Romagnoli Delia Preti 《Purinergic signalling》2009,5(1):3-19
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named
A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding
of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective
agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview
of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine
ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N
6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions.
Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1
K
i = 1050 nM, hA2A
K
i = 1550 nM, hA2B EC50 = 82 nM, hA3
K
i > 5 μM) and its 2-chloro analogue 23 (hA1
K
i = 3500 nM, hA2A
K
i = 4950 nM, hA2B EC50 = 210 nM, hA3
K
i > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay
in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide
(BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis.
This article has previously been published in issue 4/4, under doi:. 相似文献
82.
83.
Paola Zubini Barbara Zambelli Francesco Musiani Stefano Ciurli Paolo Bertolini Elena Baraldi 《Plant physiology》2009,150(3):1235-1247
84.
Merighi S Benini A Mirandola P Gessi S Varani K Leung E Maclennan S Baraldi PG Borea PA 《Purinergic signalling》2006,2(4):627-632
Downstream A3 receptor signalling plays an important role in the regulation of cell death and proliferation. Therefore, it is important to determine the molecular pathways involved through A3 receptor stimulation. The phosphatidylinositide-3-OH kinase (PI3K)/Akt and the Raf/mitogen-activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways have central roles in the regulation of cell survival and proliferation. The crosstalk between these two pathways has also been investigated. The focus of this review centres on downstream mediators of A3 adenosine receptor signalling. 相似文献
85.
Romeo Romagnoli Pier Giovanni Baraldi Maria Dora Carrion Olga Cruz-Lopez Manlio Tolomeo Stefania Grimaudo Antonietta Di Cristina Maria Rosaria Pipitone Jan Balzarini Andrea Brancale Ernest Hamel 《Bioorganic & medicinal chemistry》2010,18(14):5114-5122
The central role of microtubules in cell division and mitosis makes them a particularly important target for anticancer agents. On our early publication, we found that a series of 2-(3′,4′,5′-trimethoxybenzoyl)-3-aminobenzo[b]thiophenes exhibited strong antiproliferative activity in the submicromolar range and significantly arrested cells in the G2–M phase of the cell cycle and induced apoptosis.In order to investigate the importance of the amino group at the 3-position of the benzo[b]thiophene skeleton, the corresponding 3-unsubstituted and methyl derivatives were prepared. A novel series of inhibitors of tubulin polymerization, based on the 2-(3,4,5-trimethoxybenzoyl)-benzo[b]thiophene molecular skeleton with a methoxy substituent at the C-4, C-5, C-6 or C-7 position on the benzene ring, was evaluated for antiproliferative activity against a panel of five cancer cell lines, for inhibition of tubulin polymerization and for cell cycle effects. Replacing the methyl group at the C-3 position resulted in increased activity compared with the corresponding 3-unsubstituted counterpart. The structure–activity relationship established that the best activities were obtained with the methoxy group placed at the C-4, C-6 or C-7 position. Most of these compounds exhibited good growth inhibition activity and arrest K562 cells in the G2–M phase via microtubule depolymerization. 相似文献
86.
87.
Carlotta Pia Cristalli Chiara Zannini Giorgia Comai Olga Baraldi Vania Cuna Maria Cappuccilli Vilma Mantovani Niccolò Natali Giuseppe Cianciolo Gaetano La Manna 《Genes & genomics.》2017,39(7):689-699
Gene polymorphisms involved in homocysteine-methionine pathway result in hyperhomocysteinemia, a predisposing condition to several diseases. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate and homocysteine metabolism. The two known functional polymorphisms of MTHFR gene, 677C>T and 1298A>C have been implicated in a variety of multifactorial diseases: cardio-cerebrovascular and neurodegenerative disorders, autoimmune diseases, birth defects, diabetes, neuropsychiatric disorders, cancer and renal disease. C667T, and to a lesser extent A1298C polymorphisms, have been also reported to have a pharmacogenetic role in predicting drug toxicity in cancer and rheumatoid arthritis treatment. We review here the principal effects of the MTHFR gene variations in different clinical conditions. 相似文献
88.
Kynurenic, anthranilic, and quinolinic acid, brain tissue concentrations and indoleamine 2,3-dioxygenase [EC 1 13.11.17] activity were determined in rat brain, during pre- and postnatal development. Quinolinic acid brain tissue concentration was significantly increased at birth as compared with the prenatal level, then it declined rapidly in the postnatal period. By the contrary, kynurenic and anthranilic acids brain tissue concentrations in rat brain were significantly lower at birth as compared with those found prenatally; then kynurenic acid concentration decreased in the first postnatal week and increased thereafter, while anthranilic acid concentration increased in the first postnatal week and decreased thereafter. Indoleamine 2,3-dioxygenase [EC 1 13.11.17] activity were found unchanged in pre and post natal rat brain. The described opposite changes in quinolinic and kynurenic acids concentrations, occurring in pre- and postnatal period, despite the lack of knowledge on the precise role played by these compounds on the different neurotransmitter systems in the brain, could be involved in brain ontogenetic development. 相似文献
89.
Summary. Exposure of cultured neurons to nanomolar concentrations of terfenadine prevented the NMDA receptor-mediated early appearance
(30 min.) of toxicity signs induced by the voltage sensitive sodium channel activator veratridine. Terfenadine also provided
an histamine-insensitive protection against delayed neurotoxicity by veratridine (24 h), occurring independently of NMDA receptor
activation, while not protecting from excitotoxicity following direct exposure of neurons to glutamate. Terfenadine reduced
tetrodotoxin-sensitive inward currents, and reduced intracellular cGMP formation following veratridine exposure.
Our data suggest that nanomolar concentrations of TEF may reduce excitatory aminoacid release following neuronal depolarization
via a presynaptic mechanism involving voltage sensitive sodium channels, and therefore may be considered as a prototype for
therapeutic drugs in the treatment of diseases that involve excitatory aminoacid neurotransmission.
Received August 31, 1999 Accepted September 20, 1999 相似文献
90.
Manfredini S Baraldi PG Bazzanini R Durini E Vertuani S Pani A Marceddu T Demontis F Vargiu L La Colla P 《Nucleosides, nucleotides & nucleic acids》2000,19(4):705-722
Continuing our studies on the structure-activity relationships (SAR) of 4-iodo-1-beta-D-ribofuranosyl-3-carboxymethyl pyrazole (IPCAR), the ribofuranosyl moiety has been substituted with acyclic chains, namely 1-[(2-hydroxyethoxy)methyl]- and 1-[(1,3-dihydroxy-2-propoxy)methyl]-pyrazole derivatives (4, 5 and 8, 9 respectively), with the 2'-deoxy-beta-D-ribofuranosyl group (12 and 13) and finally with the 2',3'-dideoxy-D-glycero-pentofuranosyl-moiety (16 and 17). None of the new compounds display any interesting biological activity. 相似文献