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1.
A series of new 7-arylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 8-amino substituent in 8 position was synthesized and their 5-HT 1A, 5-HT 2A, 5-HT 6, 5-HT 7, and D 2 receptor affinities were determined. The binding study allowed identifying some potent 5-HT 1A/5-HT 2A/5-HT 7/D 2 ligands. The most interesting because of their multireceptor profile were 8-piperidine ( 30– 35) and 8-dipropylamine ( 45– 47) analogs with four and five carbon aliphatic linkers. The selected compounds 24, 31, 34, 39, 41, 43, 45, and 46 in the functional in vitro evaluation for all targeted receptors showed significant partial D 2 agonist, partial 5-HT 1A agonist, and 5-HT 2A antagonist properties. The advantageous in vitro affinity of compound 34 for 5-HT 1A and D 2 receptors has been explained by means of molecular modeling, taking into consideration its partial agonist activity towards the latter one. In behavioral studies, compounds 32 and 34 revealed antipsychotic-like properties, significantly decreasing d-amphetamine-induced hyperactivity in mice. 相似文献
2.
The structures of three new gibberellins A 30, A 48 and A 49 and a new kaurenolide, isolated from seeds of Cucurbita pepo L., were elucidated. The structures of GA 39, GA 48 and GA 49 were shown to be ent-3α,12 β-dihydroxygibberell-16-ene-7,19,20-trioic acid ( 1), ent-2α,3α,10,12α-tetrahydroxy-20-norgibberell-16-ene-7,19-dioic acid 19,10-lactone ( 5) and the epimer at C–12 of GA 48 ( 8), respectively. The kaurenolide was shown to have the structure: ent-6 β,7α,12 β-trihydroxykaur-16-en-19-oic acid 19,6-lactone ( 14). 相似文献
3.
The development of adenosine A 2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A 2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A 2A receptor. Compound F1, with an affinity of 1?μm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184?μm) without being cytotoxic at 100?μm. This compound, along with low-molecular weight compound D1 ( Ki?=?10?μm), can be easily modulated and thus considered as relevant starting points for further hit-to-lead optimisation. 相似文献
4.
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named
A 1, A 2A, A 2B and A 3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A 2B 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 A 2B 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 A 2B 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-, C 2-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]-9 H-purin-9-yl}-N-ethyl- β-D-ribofuranuronamide ( 19, hA 1
K
i = 1050 nM, hA 2A
K
i = 1550 nM, hA 2B EC 50 = 82 nM, hA 3
K
i > 5 μM) and its 2-chloro analogue 23 (hA 1
K
i = 3500 nM, hA 2A
K
i = 4950 nM, hA 2B EC 50 = 210 nM, hA 3
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 hA 2B 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, hA 1, hA 2A, hA 3 EC 50 > 10 μM; hA 2B EC 50 = 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
5.
Abstract Three novel nucleosides 1, 2, and 3 were prepared that contained side chains at the 2-position of adenosine. Compound 1 was shown to be the most selective A 2a receptor agonist reported to date having an A 1/A 2 ratio of 2400. In addition, compound 1 was shown to reduce blood pressure in rats and dogs with only minimal effects on heart rate. 相似文献
6.
Abstract Adenosine derivatives bearing in 2-position the ( R, S)- phenylhydroxypropynyl chain were evaluated for their potency at human A 2B adenosine receptor, stably transfected on CHO cells, on the basis that ( R, S)-2-phenylhydroxy-propynyl-5′-N-ethylcarboxyamidoadenosine [( R, S)-PHPNECA] was found to be a good agonist at the A 2B receptor subtype. Biological studies demonstrated that the presence of small alkyl groups in N 6-position of these molecules are well tolerated, whereas large groups abolished A 2B potency. On the other hand, the presence of an ethyl group in the 4′-carboxamido function seems to be optimal, the ( S)-PHPNECA resulting the most potent agonist at A 2B receptor reported so far. 相似文献
7.
It is a pleasure to contribute to the special issue published in honor of Vladimir Skulachev, a distinguished scientist who greatly contributes to maintain a high standard of biochemical research in Russia. A more particular reason can be found in his work (Artzabanov, V. Y., Konstantinov, A. A., and Skulachev, V. P. (1978) FEBS Lett., 87, 180–185), where observations anticipating some ideas presented in my article were reported. Cytochrome c oxidase exhibits protonmotive, redox linked allosteric cooperativity. Experimental observations on soluble bovine cytochrome c oxidase are presented showing that oxido-reduction of heme a/Cu A and heme a
3/Cu B is linked to deprotonation/protonation of two clusters of protolytic groups, A 1 and A 2, respectively. This cooperative linkage (redox Bohr effect) results in the translocation of 1 H +/oxidase molecule upon oxido-reduction of heme a/Cu A and heme a
3/Cu B, respectively. Results on liposome-reconstituted oxidase show that upon oxidation of heme a/Cu A and heme a
3/Cu B protons from A 1 and A 2 are released in the outer aqueous phase. A 1 but not A 2 appears to take up protons from the inner aqueous space upon reduction of the respective redox center. A cooperative model is presented in which the A 1 and A 2 clusters, operating in close sequence, constitute together the gate of the proton pump in cytochrome c oxidase.Translated from Biokhimiya, Vol. 70, No. 2, 2005, pp. 220–230.Original Russian Text Copyright © 2005 by Papa.This revised version was published online in April 2005 with corrections to the post codes. 相似文献
8.
Purpose: Eight A 2AR variants are reported in humans while no A 2AR isoforms in pigs. The aim of this study was to evaluate potential isoforms presence in cardiac pig tissue to better define possible involvement of A 2AR in the cardiovascular pathophysiology. Materials and methods: In adult male minipigs ( n?=?4) left ventricular dysfunction (LVD) was induced by pacing at 200 bpm in the right ventricular (RV) apex. In these animals and in sham operated pigs (C-SHAM, n?=?4) cardiac tissue was collected from LV-septal wall (LV-SW)-close to pacing site-and from lateral (opposite) site (LV-OSW). A 2AR specific primers, derived from Sus scrofa AY772412 sequence, were used for Real-Time PCR. The DNA was sequenced using the Sanger method. Histological analysis was also performed. Results: In LV-SW of LVD minipigs the A 2AR melting curves were characterized by a sharp peak between 87 and 91?°C (short isoform, 1–94?bp) on the right of the principal peak corresponding to a long A 2AR isoform (GenBank: JQ229674.1) 1–213?bp. As for C-SHAM only one peak was observed in LV-OSW region of LVD animals. The short isoform had an alternative promoter region and a specific translated protein. Histology showed in LVD-LV-SW prominent Purkinje cells compared to LV-OSW and C-SHAM. No difference in A 2AR expression was observed between LVD animals and C-SHAM although a slight decrease was observed in LVD-LV-OSW. Conclusions: The presence of two different isoforms in the myocardium close to the insertion of pacing is suggestive of a differential state-specific expression of A 2AR in cardiac tissue. 相似文献
9.
New 7-amino-2-phenylpyrazolo[4,3- d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A 1 and/or A 2A receptor subtypes. On the whole, the novel derivatives 1– 24 shared scarce or no affinities for the off-target hA 2B and hA 3 ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity ( Ki =?150?nM) and the best selectivity for the hA 2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA 2A ( Ki =?123?nM) and A 1 AR affinity ( Ki =?25?nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity ( Ki =?11?nM) and good selectivity for the hA 1 AR. The 5-(N 4-substituted-piperazin-1-yl) derivatives 15– 24 bind the hA 1 AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis. 相似文献
10.
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named
A 1, A 2A, A 2B and A 3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A 2B 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 A 2B 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 A 2B 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-, C 2-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]-9 H-purin-9-yl}-N-ethyl- β-D-ribofuranuronamide ( 19, hA 1
K
i = 1050 nM, hA 2A
K
i = 1550 nM, hA 2B EC 50 = 82 nM, hA 3
K
i > 5 μM) and its 2-chloro analogue 23 (hA 1
K
i = 3500 nM, hA 2A
K
i = 4950 nM, hA 2B EC 50 = 210 nM, hA 3
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 hA 2B 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, hA 1, hA 2A, hA 3 EC 50 > 10 μM; hA 2B EC 50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis. 相似文献
11.
Gibberellin A 59 has been isolated from immature seeds of Canavalia gladiata (sword bean) and its structure was determined to be Δ 2-gibberellin A 21 ( 1). 相似文献
12.
The presence of phospholipase A activity was detected in three dermatophytes: Microsporum cookei, Trichophyton mentagrophytes, and Epidermophyton floccosum. The activity was always higher in T. mentagrophytes than in M. cookei and E. floccosum. All exhibited phospholipase A 1 and A 2 activities, but the activity was largely A 2 in M. cookei and A 1 in E. floccosum. T. mentagrophytes possessed almost equal activities of phospholipase A 1 and A 2. 相似文献
13.
Previously, we have reported that the coronary reactive hyperemic response was reduced in adenosine A2A receptor-null (A2AAR?/?) mice, and it was reversed by the soluble epoxide hydrolase (sEH) inhibitor. However, it is unknown in aortic vascular response, therefore, we hypothesized that A2AAR-gene deletion in mice (A2AAR?/?) affects adenosine-induced vascular response by increase in sEH and adenosine A1 receptor (A1AR) activities. A2AAR?/? mice showed an increase in sEH, AI AR and CYP450-4A protein expression but decrease in CYP450-2C compared to C57Bl/6 mice. NECA (adenosine-analog) and CCPA (adenosine A1 receptor-agonist)-induced dose-dependent vascular response was tested with t-AUCB (sEH-inhibitor) and angiotensin-II (Ang-II) in A2AAR?/? vs. C57Bl/6 mice. In A2AAR?/?, NECA and CCPA-induced increase in dose-dependent vasoconstriction compared to C57Bl/6 mice. However, NECA and CCPA-induced dose-dependent vascular contraction in A2AAR?/? was reduced by t-AUCB with NECA. Similarly, dose-dependent vascular contraction in A2AAR?/? was reduced by t-AUCB with CCPA. In addition, Ang-II enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR?/? with NECA. Similarly, the dose-dependent vascular contraction in A2AAR?/? was also enhanced by Ang-II with CCPA. Further, t-AUCB reduced Ang-II-enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR?/? mice. Our data suggest that the dose-dependent vascular contraction in A2AAR?/? mice depends on increase in sEH, A1AR and CYP4A protein expression. 相似文献
14.
Two new gibberellins A 50 and A 52 were isolated from seeds of Lagenaria leucantha Rusby var. clavata Makino. Their structures were shown to be ent-2α,3α,10,llα-tetrahydroxy-20-norgibberell-16-ene-7,19-dioic acid 19,10-lactone ( 1) and ent-2α,3α,11 β20-tetrahydroxy-gibberell-16-ene-7,19-dioic acid 19,20-lactone ( 10), respectively. 相似文献
15.
Summary A simple and rapid screening method for microorganisms with phospholipase A 1, A 2 and C activities using agar plate and gas chromatography (GC) method was successfully carried out. In agar plate method, soy bean lecithin and taurocholic acid were used as carbon source and emulsifier, respectively. In this agar plate method, microorganisms with phospholipase A 1 and A 2 or C activity produce a halo around the colony and two kinds(A's and C) of microorganisms are clearly distinguished by turbidity of the halo. Microorganisms with phospholipase A 1 and A 2 activity is simply distinguished by GC using a synthetic phospholipid containing different fatty acid at sn-1 and sn-2 position. 相似文献
16.
A new series of 2,6,9-trisubstituted adenines ( 5–14) have been prepared and evaluated in radioligand binding studies for their affinity at the human A 1, A 2A and A 3 adenosine receptors and in adenylyl cyclase experiments for their potency at the human A 2B subtype. From this preliminary study the conclusion can be drawn that introduction of bulky chains at the N
6 position of 9-propyladenine significantly increased binding affinity at the human A 1 and A 3 adenosine receptors, while the presence of a chlorine atom at the 2 position resulted in a not univocal effect, depending
on the receptor subtype and/or on the substituent present in the N
6 position. However, in all cases, the presence in the 2 position of a chlorine atom favoured the interaction with the A 2A subtype. These results demonstrated that, although the synthesized compounds were found to be quite inactive at the human
A 2B subtype, adenine is a useful template for further development of simplified adenosine receptor antagonists with distinct
receptor selectivity profiles. 相似文献
17.
The nucleotide sequence of cDNA encoding the glycinin A 2B 1a subunit from var. Shirotsurunoko was determined and compared with that in the case of var. Bonminori. The comparison showed six nucleotide substitutions in the coding sequence, one of which results in one amino acid replacement, and three in the 3'-noncoding region. These differences indicate the occurrence of polymorphism of the glycinin A 2B 1a subunit gene between the cultivars. The present data together with the previous results indicating the polymorphism of the A 1aB 1b subunit gene [(Utsumi et al., J. Agric. Food Chem., 35, 210 (1987)] suggest that the polymorphism is a general property of glycinin subunit genes. The expression of cDNAs encoding the A 2B 1a and A 1aB 1b subunits was examined. The results obtained in both in vivo- and in vitro-expression experiments indicate that the resultant products were readily degraded. 相似文献
18.
Antimycinone A 3, which is a neutral fragment of mild alkaline hydrolysate of antimycin A 3, and its stereoisomers were synthesized stereoselectively from methyl trans-2- n-butylpent-3-enoate or methyl cis-2- n-butylpent-3-enoate, and natural antimycinone A 3 was proved to possess Hα-Hβ and Hβ-H γ trans configuration. 相似文献
19.
We estimated the subsite structure of α-amylase II (TVA II) from Thermoactinomyces vulgaris R-47 expressed in Escherichia coli. TVA II has eight subsites, and the catalytic site is between the 5th and 6th subsite from the non-reducing end side. The subsite affinities, A -5, A -4, A -3, A -2, (A -1+A +1), A +2, and A +3, were calculated to be -0.35, 0.93, 0.55, 2.56, 1.18, 1.71, and 0.01 kcal mol -1, respectively. 相似文献
20.
Wittwer , S. H., and M. J. Bukovac . (Michigan State U., E. Lansing.) Quantitative and qualitative differences in plant response to the gibberellins. Amer. Jour. Bot. 49(5): 524–529. Illus. 1962.—The comparative biological activities of gibberellins A 1 through A 9 were evaluated, over a wide concentration range and in several test systems. All gibberellins were effective in promoting stem elongation of dwarf peas ( Pisum sativum), and, with the exception of A 8, epicotyl growth in Phaseolus vulgaris. Elongation of Cucumis sativus seedlings was strikingly greater with A 4, A 7, and A 9 than with the other gibberellins. With mutant dwarfs of Zea mays, A 5 and A 9 were the most active gibberellins for d3 and d5, and relatively ineffective compared to A 3 on d1. Gibberellins A 2, A 7, and A 8 were less effective than A 3 on all dwarfs. Qualitative and quantitative differences among the gibberellins were noted on seedstalk elongation and flowering of Lactuca sativa, with A 3 the most active followed by A 1, A 7, A 4, and A 9. No flowering or seedstalk elongation occurred with A 2, A 6 or A 8. Parthenocarpic fruit growth in Lycopersicon esculentum was a function of dosage with all gibberellins. At the lowest levels, A 5 and A 7 were the most active, while at the highest levels all gibberellins with the exception of A 8 were equally effective. The results suggest a high degree of species and response specificity among the known fungal and higher plant gibberellins, and demonstrate the importance of utilizing a wide spectrum of plant responses and dosage levels in the biological assay of plant extracts for native gibberellins. 相似文献
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