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1.
Hui Li Heng Chin Fei Chee Chun Keng Thy Jia Ti Tee Sek Peng Chin Deron R. Herr Michael J. C. Buckle Ian C. Paterson Stephen W. Doughty Noorsaadah Abd. Rahman Lip Yong Chung 《Chemical biology & drug design》2019,93(2):132-138
Compounds with activity at serotonin (5‐hydroxytryptamine) 5‐HT2 and α1 adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5‐HT2 and adrenergic α1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5‐HT2 and α1 receptors with (R)‐isolaureline showing the greatest potency (pKb = 8.14 at the 5‐HT2C receptor). Both (R)‐ and (S)‐glaucine also antagonized α1 receptors, but they behaved very differently to the other compounds at 5‐HT2 receptors: (S)‐glaucine acted as a partial agonist at all three 5‐HT2 receptor subtypes, whereas (R)‐glaucine appeared to act as a positive allosteric modulator at the 5‐HT2A receptor. 相似文献
2.
《Chemical biology & drug design》2018,92(3):1647-1656
α‐Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α‐glucosidase and PTP1B may be potential candidates for type 2 diabetes therapy. In this work, three series of novel N‐aryl‐ω‐(benzoazol‐2‐yl)‐sulfanylalkanamides were synthesized and assayed for their α‐glucosidase and PTP1B inhibitory activities, respectively. Compound 3l , exhibiting the most effective α‐glucosidase inhibitory activity (IC50 = 10.96 μm ( 3l ), IC50 = 51.32 μm (Acarbose), IC50 = 18.22 μm (Ursolic acid)) and potent PTP1B inhibitory activity (IC50 = 13.46 μm ( 3l ), IC50 = 14.50 μm (Ursolic acid)), was identified as a novel dual inhibitor of α‐glucosidase and PTP1B. Furthermore, 3l is a highly selective PTP1B inhibitor because no inhibition was showed by 3l at 100 μm against PTP‐MEG2, TCPTP, SHP2, or SHP1. Subsequent kinetic analysis revealed 3l inhibited α‐glucosidase in a reversible and mixed manner. Molecular docking study indicated that hydrogen bonds, van der Waals, charge interactions and Pi‐cation interactions all contributed to affinity between 3l and α‐glucosidase/PTP1B. 相似文献
3.
Synthesis,in vitro evaluation and molecular docking studies of novel coumarin‐isatin derivatives as α‐glucosidase inhibitors
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Guangcheng Wang Jing Wang Dianxiong He Xin Li Juan Li Zhiyun Peng 《Chemical biology & drug design》2017,89(3):456-463
This study synthesized a series of novel coumarin‐isatin derivatives and evaluated them for α‐glucosidase inhibitory activity. The majority of the screened compounds exhibited excellent inhibition activities with IC50 values of 2.56 ± 0.08–268.79 ± 3.04 μm , when compared to acarbose. Among the newly derivatives, compound 5p was found to be the most active compound in the library of coumarin‐isatin derivatives. Furthermore, enzyme kinetic studies showed that compound 5p is a non‐competitive inhibitor with a Ki of 2.14 μm . Molecular docking analysis revealed the existence of hydrophobic and hydrogen interactions between compound 5p and the active site of α‐glucosidase. Our results indicate that coumarin‐isatin derivatives as a new class of α‐glucosidase inhibitors. 相似文献
4.
The first total synthesis of benzophenone O‐glycosides (iriflophenone 2‐O‐α‐L ‐rhamnopyranoside: 1 and aquilarisinin: 2 ) isolated from the leaves of Aquilaria sinensis and related new derivatives ( 3 – 12 ) was accomplished through suitable protecting group manipulations and glycosylation starting from commercially available L ‐rhamnose, D ‐glucose, D ‐galactose, D ‐mannose, D ‐xylose, and 1,3,5‐trihydroxybenzene. All synthesized benzophenone O‐glycosides were evaluated for their inhibitory activities against α‐glucosidase. Of these, benzophenone O‐glycosides 4 and 10 exhibited the most potent inhibitory activity in vitro against α‐glucosidase with IC50 values of 168.7 ± 13.9 and 210.1 ± 23.9 µM, respectively, when compared with that of the positive control acarbose with an IC50 value of 569.3 ± 49.7 µM. 相似文献
5.
Lingling Zhang Xiaojun Wang Yifan Wang Anthony Yiu‐Ho Woo Weizhong Zhu 《Clinical and experimental pharmacology & physiology》2017,44(2):285-293
Cardiac fibrosis is a pathological feature commonly found in hearts exposed to haemodynamic orneurohormonal stress. Elevated levels of arginine vasopressin (AVP) are closely associated with the progression of heart failure and could be an underlying cause of cardiac fibrosis. The aim of this study is to characterize the effect of AVP on neonatal rat cardiac fibroblasts (NRCFs) and to illustrate its signalling mechanism. The proliferative effect of AVP was assessed by methylthiazolyldiphenyl‐tetrazolium assay and 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation assay, and the amounts of cellular signalling proteins α‐smooth muscle actin (α‐SMA), matrix metalloproteinase (MMP) 2, MMP9, and phosphorylated ERK1/2 were determined by western blotting. AVP, in a time‐ and concentration‐dependent manner, promoted NRCF proliferation and the expression of MMP2 and MMP9. Inhibition of G protein‐coupled receptor kinase2 (GRK2) by the inhibitory peptide GRK2‐Ct or knock‐down of GRK2 suppressed AVP‐induced BrdU incorporation and the expression of MMP2 and α‐SMA in NRCFs. Moreover, shRNA‐mediated silencing of β‐arrestin1 or β‐arrestin 2 abolished AVP‐induced BrdU incorporation and MMP2 expression. AVP‐induced NRCF proliferation depended on the phosphorylation of ERK1/2, and inhibition of GRK2 or silencing of β‐arrestins blocked AVP‐induced ERK1/2 phosphorylation. The effects of AVP on NRCF proliferation and α‐SMA expression were blocked by SR45059, a vasopressin receptor type1A (V1AR) selective antagonist. In conclusion, AVP promotes NRCF proliferation through V1AR‐mediated GRK2/β‐arrestin/ERK1/2 signalling. 相似文献
6.
José‐Ángel García‐Pedraza Mónica García‐Domingo Miriam Gómez‐Roso Alicia Rodríguez‐Barbero María‐Luisa Martín Asunción Morán 《Clinical and experimental pharmacology & physiology》2017,44(12):1224-1231
5‐hydroxytryptamine (5‐HT) modulates noradrenergic activity in different cardiovascular territories, but its effect on the mesenteric vasopressor outflow has not yet been clarified. This study investigated the in vivo serotonergic influence, characterizing 5‐HT receptors implicated, in sympathetic innervation of mesenteric vasculature. Wistar rats were anaesthetised and prepared for the in situ autoperfused rat mesentery, monitoring systemic blood pressure (SBP), heart rate (HR) and mesenteric perfusion pressure (MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency‐dependent increases in MPP (9 ± 1.6, 25.7 ± 3.9 and 60.2 ± 5 mmHg for 2, 4 and 8 Hz, respectively), without altering SBP or HR. 5‐HT (1‐25 μg/kg), 5‐carboxamidotryptamine (5‐HT1/7 agonist; 25 μg/kg) or L‐694,247 (5‐HT1D agonist; 1‐25 μg/kg) i.a. bolus inhibited vasopressor responses by mesenteric nerves electrical stimulation, unlike i.a. bolus of agonists 8‐OH‐DPAT (5‐HT1A), CGS‐12066B (5‐HT1B), BRL 54443 (5‐HT1e/1F), α‐methyl‐5‐HT (5‐HT2), 1‐PBG (5‐HT3), cisapride (5‐HT4) or AS‐19 (5‐HT7) (25 μg/kg each). Interestingly, i.a. L‐694,247 (25 μg/kg) also reduced the exogenous norepinephrine‐induced vasoconstrictions. Pretreatment with selective 5‐HT1D receptor antagonist, LY310762 (1 mg/kg, i.v.), completely abolished L‐694,247‐ and 5‐HT‐induced mesenteric sympathoinhibition. Furthermore, ELISA analysis confirmed 5‐HT1D receptors expression in mesenteric artery. These findings suggest that serotonergic mechanisms‐induced sympathoinhibition of mesenteric noradrenergic outflow is mediated by pre and/or postjunctional 5‐HT1D receptors. 相似文献
7.
Potencies of vitamin D analogs, 1α‐hydroxyvitamin D3, 1α‐hydroxyvitamin D2 and 25‐hydroxyvitamin D3, in lowering cholesterol in hypercholesterolemic mice in vivo
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Holly P. Quach Tamara Dzekic Paola Bukuroshi K. Sandy Pang 《Biopharmaceutics & drug disposition》2018,39(4):196-204
Vitamin D3 and the synthetic vitamin D analogs, 1α‐hydroxyvitamin D3 [1α(OH)D3], 1α‐hydroxyvitamin D2 [1α(OH)D2] and 25‐hydroxyvitamin D3 [25(OH)D3] were appraised for their vitamin D receptor (VDR) associated‐potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D3 and 1α(OH)D2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25‐dihydroxyvitamin D3 [1,25(OH)2D3] and 1α,25‐dihydroxyvitamin D2 [1,25(OH)2D2], respectively. 1α(OH)D2 may also be activated by CYP24A1 to 1α,24‐dihydroxyvitamin D2 [1,24(OH)2D2], another active VDR ligand. 25(OH)D3, the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D3, is activated by CYP27B1 in the kidney to 1,25(OH)2D3. In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7α‐hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D3 > 1248 nmol/kg 25(OH)D3 (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D3. Except for 1.21 nmol/kg 1α(OH)D2 that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH)2D3 formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1α(OH)D3 and 25(OH)D3 exhibit cholesterol lowering properties upon activation to 1,25(OH)2D3: 1α(OH)D3 is rapidly activated by liver enzymes and 25(OH)D3 is slowly activated by renal Cyp27b1 in mouse. 相似文献
8.
Tiina Koskinen Antti Haapalinna Jouni Sirvi 《Basic & clinical pharmacology & toxicology》2003,92(5):214-225
Abstract: The activation of 5‐HT2A receptors has been shown to enhance the probability of premature responding, regarded as a form of motor impulsive behaviour. At the behavioural level, the interaction of α‐adrenoceptors and 5‐HT2 receptors has been linked to head twitch behaviour, regarded as an experimental model of compulsive behaviour. The aim was to determine whether the probability of premature responding induced by an excess activation of 5‐HT2A receptors can be modulated by the blockade of α1‐ or α2‐ adrenoceptors. In the experiments, the 5‐choice serial reaction time task was used to measure attention and response control of the rats. The experiments assessed the effects of (±)‐1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI) 0.1–0.2 mg/kg subcutaneously, a 5‐HT2A/2C agonist, and prazosin, an α1–adrenoceptor antagonist, alone or in combination, on the performance of rats. In an additional experiment to examine the possible role of the α2–adrenoceptors, a potent, selective and specific α2–adrenoceptor antagonist, atipamezole, was given alone or in combination with DOI. Results showed that DOI increased the probability of premature responses, but it did not affect the choice accuracy. Prazosin (0.1 or 0.3 mg/kg, subcutaneously), given on its own had no effects on probability of responding prematurely, but prazosin (0.3 mg/kg.) was able to attenuate the DOI‐induced responding. Atipamezole (0.1 mg/kg, s.c.) did not attenuate the effect of DOI on probability of premature responding. When given at lower doses, DOI (0.03 mg/kg) and atipamezole (0.03 mg/kg) synergistically increased the probability of premature responding, whereas a higher dose of atipamezole (0.3 mg/kg) on its own increased the probability of responding prematurely, but this effect was not additive to that of 0.1 mg/kg DOI. These data indicate that 5‐HT2 receptor activation enhances impulsive responding and this effect can be diminished by the blockade of α1‐adrenoceptors. Atipamezole, an α2‐antagonist, enhances the probability of premature responding and shares the mechanism of action with the 5‐HT2 agonist in this respect. These results provide evidence for an interaction between the serotonergic 5‐HT2 receptors and α‐adrenoceptors in the modulation of response control to the motor impulsivity type of behaviour (premature responding) in addition to that of compulsory behaviour (head shakes) found previously. 相似文献
9.
Vani Munusamy Beow Keat Yap Michael J. C. Buckle Stephen W. Doughty Lip Yong Chung 《Chemical biology & drug design》2013,81(2):250-256
Selective blockade of the serotonin 5‐HT2A receptor is a useful therapeutic approach for a number of disorders, including schizophrenia, insomnia and ischaemic heart disease. A series of aporphines were docked into a homology model of the rat 5‐HT2A receptor using AutoDock. Selected compounds with high in silico binding affinities were screened in vitro using radioligand‐binding assays against rat serotonin (5‐HT1A and 5‐HT2A) and dopamine (D1 and D2) receptors. (R)‐Roemerine and (±)‐nuciferine were found to have high affinity for the 5‐HT2A receptor (Ki = 62 and 139 nm , respectively), with (R)‐roemerine showing 20‐ to 400‐fold selectivity for the 5‐HT2A receptor over the 5‐HT1A, D1 and D2 receptors. Investigation into the ligand–receptor interactions suggested that the selectivity of (R)‐roemerine is due to it having stronger H‐bonding and dipole–dipole interactions with several of the key residues in the 5‐HT2A receptor‐binding site. 相似文献
10.
Elisa Magli Ewa Kdzierska Agnieszka A. Kaczor Beatrice Severino Angela Corvino Elisa Perissutti Francesco Frecentese Irene Saccone Paola Massarelli Ewa Gibua‐Tarowska Jolanta H. Kotliska Vincenzo Santagada Giuseppe Caliendo Ferdinando Fiorino 《Archiv der Pharmazie》2019,352(5)
N′‐Cyanoisonicotinamidine and N′‐cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinities to the 5‐HT1A, 5‐HT2A, and 5‐HT2C receptors were evaluated. Several of the newly synthesized compounds, tested by binding studies, showed nanomolar affinity at the 5‐HT1A and 5‐HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1, and α2). Compound 8e (Ki = 21.4 nM) was the most affine for the 5‐HT2C receptor, showing, at the same time, a high selectivity with respect to the other receptors analyzed. Compounds 4a and 4c , instead, showed an interesting mixed 5‐HT1A/5‐HT2C activity with Ki values of 21.3/11.5 and 23.2/6.48 nM, respectively. The compounds with better affinity and selectivity binding profiles toward 5‐HT2C ( 4a , 4c , 8b , and 8e ) were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that compounds 4a , 8b , and 8e exerted antidepressant‐like effects and 4a and 8e revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compound seems to be 4a , which displayed antipsychotic‐, antidepressant‐ and anxiolytic‐like properties. No side effects, like catalepsy, motor‐impairment or ethanol‐potentiating effects, were observed after the injection of the tested compounds. 相似文献
11.
Ute Mühlhausen Johannes Ermert Matthias M. Herth Heinz H. Coenen 《Journal of labelled compounds & radiopharmaceuticals》2009,52(1):6-12
In some psychiatric disorders 5‐HT2A receptors play an important role. In order to investigate those in vivo there is an increasing interest in obtaining a metabolically stable, subtype selective and high affinity radioligand for receptor binding studies using positron emission tomography (PET). Combining the excellent in vivo properties of [11C]MDL 100907 for PET imaging of 5‐HT2A receptors and the more suitable half‐life of fluorine‐18, MDL 100907 was radiofluorinated in four steps using 1‐(2‐bromoethyl)‐4‐[18F]fluorobenzene as a secondary labelling precursor. The complex reaction required an overall reaction time of 140 min and (±)‐[18F]MDL 100907 was obtained with a specific activity of at least 30 GBq/µmol (EOS) and an overall radiochemical yield of 1–2%. In order to verify its binding to 5‐HT2A receptors, in vitro rat brain autoradiography was conducted showing the typical distribution of 5‐HT2A receptors and a very low non‐specific binding of about 6% in frontal cortex, using ketanserin or spiperone for blocking. Thus, [18F]MDL 100907 appears to be a promising new 5‐HT2A PET ligand. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献
12.
Return of the lysergamides. Part I: Analytical and behavioural characterization of 1‐propionyl‐d‐lysergic acid diethylamide (1P‐LSD)
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Simon D. Brandt Pierce V. Kavanagh Folker Westphal Alexander Stratford Simon P. Elliott Khoa Hoang Jason Wallach Adam L. Halberstadt 《Drug testing and analysis》2016,8(9):891-902
1‐Propionyl‐d‐lysergic acid diethylamide hemitartrate (1P‐LSD) has become available as a ‘research chemical’ in the form of blotters and powdered material. This non‐controlled derivative of d‐lysergic acid diethylamide (LSD) has previously not been described in the published literature despite being closely related to 1‐acetyl‐LSD (ALD‐52), which was developed in the 1950s. This study describes the characterization of 1P‐LSD in comparison with LSD using various chromatographic and mass spectrometric methods, infrared and nuclear magnetic resonance spectroscopy. An important feature common to LSD and other serotonergic hallucinogens is that they produce 5‐HT2A‐receptor activation and induce the head‐twitch response (HTR) in rats and mice. In order to assess whether 1P‐LSD displays LSD‐like properties and activates the 5‐HT2A receptor, male C57BL/6 J mice were injected with vehicle (saline) or 1P‐LSD (0.025–0.8 mg/kg, IP) and HTR assessed for 30 min using magnetometer coil recordings. It was found that 1P‐LSD produced a dose‐dependent increase in HTR counts, and that it had ~38% (ED50 = 349.6 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). Furthermore, HTR was abolished when 1P‐LSD administration followed pretreatment with the selective 5‐HT2A receptor antagonist M100907 (0.1 mg/kg, SC), which was consistent with the concept that the behavioural response was mediated by activation of the 5‐HT2A receptor. These results indicate that 1P‐LSD produces LSD‐like effects in mice, consistent with its classification as a serotonergic hallucinogen. Nevertheless, the extent to which 1P‐LSD might show psychoactive effects in humans similar to LSD remains to be investigated. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
13.
Pharmacological evidence that 5‐HT1D activation induces renal vasodilation by NO pathway in rats
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José‐Ángel García‐Pedraza Mónica García María‐Luisa Martín Asunción Morán 《Clinical and experimental pharmacology & physiology》2015,42(6):640-647
5‐HT is a powerful vasoconstrictor substance in renal vasculature (mainly by 5‐HT2 activation). Nevertheless, 5‐HT is notable for its dual cardiovascular effects, producing both vasodilator and vasoconstrictor actions. This study aimed to investigate whether, behind the predominant serotonergic vasoconstrictor action, THE 5‐HT system may exert renal vasodilator actions, and, if so, characterize the 5‐HT receptors and possible indirect pathways. Renal perfusion pressure (PP), systemic blood pressure (SBP) and heart rate (HR) measurement in in situ autoperfused rat kidney was determined in phenylephrine infused rats. Intra arterial (i.a.) bolus administration of 5‐HT (0.00000125–0.1 μg/kg) decreased renal PP in the presence of a phenylephrine continuous infusion (phenylephrine‐infusion group), without modifying SBP or HR. These vasodilator responses were potentiated by 5‐HT2 antagonism (ritanserin, 1 mg/kg i.v.), whereas the responses were abolished by 5‐HT1/7 antagonist (methiothepin, 100 μg/kg i.v.) or 5‐HT1D antagonist (LY310762, 1 mg/kg i.v.). The i.a. administration (0.00000125 to 0.1 μg/kg) of 5‐CT or L‐694,247 (5‐HT1D agonist) mimicked 5‐HT vasodilator effect, while other agonists (1‐PBG, α‐methyl‐5‐HT, AS‐19 (5‐HT7), 8‐OH‐DPAT (5‐HT1A) or CGS‐12066B (5‐HT1B)) did not alter baseline haemodynamic variables. L‐694,247 vasodilation was abolished by i.v. bolus of antagonists LY310762 (5‐HT1D, 1 mg/kg) or L‐NAME (nitric oxide, 10 mg/kg), but not by i.v. bolus of indomethacin (cyclooxygenase, 2 mg/kg) or glibenclamide (ATP‐dependent K+ channel, 20 mg/kg). These outcomes suggest that 5‐HT1D activation produces a vasodilator effect in the in situ autoperfused kidney of phenylephrine‐infusion rats mediated by the NO pathway. 相似文献
14.
Alexandre V. Ivachtchenko Eugene B. Frolov Oleg D. Mitkin Volodymyr M. Kysil Alexander V. Khvat Sergey E. Tkachenko 《Archiv der Pharmazie》2009,342(12):740-747
Synthesis, biological evaluation, and structure‐activity relationships (SAR) for a series of novel γ‐carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro‐γ‐carboline 5b (2,8‐dimethyl‐5‐[cis‐2‐pyridin‐3‐ylvinyl]‐2,3,4,5‐tetrahydro‐carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H1 and serotonin 5‐HT6 receptors (IC50 < 0.45 μM and IC50 = 0.73 μM, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity. 相似文献
15.
《Journal of labelled compounds & radiopharmaceuticals》2005,48(2):149-164
The partial ergoline LY228729 (1) which was a potent 5HT1A agonist has been studied clinically. Somewhat later, a related analog, (S)‐di‐n‐propyl‐(8‐isoxazol‐5‐yl‐1,2,3,4‐tetrahydronaphthalen‐2‐yl)amine (2a) which in addition to potent 5HT1A agonist activity was a muscarinic antagonist, was chosen for clinical development for use in the treatment of irritable bowel syndrome. In the course of pre‐clinical evaluation of 2a , radiolabeled material was required for ADME studies. In this paper, we have discussed the preparation of 2a and 2b (the C‐14‐labeled isotopomer of 2a ). Copyright © 2005 John Wiley & Sons, Ltd. 相似文献
16.
《Drug testing and analysis》2017,9(5):778-787
This article reports on the analytical properties of five pyrrolidinyl substituted cathinones: α ‐pyrrolidinononaphenone (α ‐PNP, 1 ), 4‐chloro‐α ‐pyrrolidinopropiophenone (4‐Cl‐α ‐PPP, 2 ), 4‐chloro‐α ‐pyrrolidinovalerophenone (4‐Cl‐α ‐PVP, 3 ), 5‐dihydrobenzofuranpyrovalerone (5‐DBFPV, 4 ), and 2‐(pyrrolidin‐1‐yl)‐1‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)hexan‐1‐one (β ‐THNPH, 5 ). These identifications were based on liquid chromatography–quadrupole time‐of‐flight‐mass spectrometry (LC–QTOF–MS), gas chromatography–mass spectrometry (GC–MS) and nuclear magnetic resonance spectroscopy (NMR). To our knowledge, no analytical data about α ‐PNP, 4‐Cl‐α ‐PPP, 4‐Cl‐α ‐PVP, and β ‐THNPH have appeared until now, making this the first report on these compounds. Moreover, in order to study the collision‐induced dissociation (CID) characteristic fragmentation routes of pyrrolidinyl substituted cathinones, a total number of 13 pyrrolidinyl substituted cathinones were selected and discussed. The major fragmentation pathways under CID mode are produced, leading to the formation of characteristic ions. Product ions of [M‐C4H9N]+ and CnH2nN+ indicate the presence of pyrrolidinyl substitution. Characteristic fragments are also produced via the cleavages of the CH–N(CH2)4 bond and the CO‐CHN bond. Copyright © 2016 John Wiley & Sons, Ltd. 相似文献
17.
A novel series of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazides were synthesized and studied for their α‐glucosidase inhibition activity. Most of the synthesized compounds exhibited potential α‐glucosidase inhibition activity with IC50 values ranging from 0.96 ± 0.02 to 32.86 ± 0.73 µg/ml. Among them, compounds 3e and 4e , having a methoxy group on the coumarin ring, proved to be the most potent ones, showing an enzyme inhibition activity with IC50 = 0.96 ± 0.02 and 1.44 ± 0.06 µg/ml, respectively. The kinetic study through Lineweaver–Burk plots revealed that the inhibition mechanism of the most active compounds 3d, 3e, 4d , and 4e , on the α‐glucosidase activity, was found to be in the competitive mode. 相似文献
18.
Chaw‐Chi Chiu Yea‐Wen Chen Jiunn‐Ren Wu Young‐Tso Lin Ing‐Jun Chen Jwu‐Lai Yeh 《Drug development research》2002,55(2):104-117
A vanillylamide‐based propanolamine derivative, KMUP 880708, was first investigated both in vivo and in vitro. KMUP 880708 (0.1, 0.5, 1.0, and 2.0 mg kg–1, iv) produced dose‐dependent hypotensive and bradycardia responses in pentobarbital‐anesthetized Wistar rats. KMUP 880708 (0.1, 0.5, and 1.0 mg kg–1, iv) also markedly inhibited both the tachycardia effects induced by (–)isoproterenol and arterial pressor responses induced by phenylephrine. KMUP 880708 competitively antagonized (–)isoproterenol‐induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses on isolated guinea pig tissues. The apparent pA2 values for KMUP 880708 was 7.82 ± 0.06 in the right atria, 7.51 ± 0.13 in the left atria, and 6.31 ± 0.07 in the trachea, respectively, indicating that KMUP 880708 was selective β1‐adrenoceptor blocker. In thoracic aorta experiments, KMUP 880708 also produced a competitive antagonism of norepinephrine‐induced contraction with pA2 value of 7.92 ± 0.52, indicating that KMUP 880708 was α‐adrenoceptor antagonist. In isolated rat thoracic aorta, KMUP 880708 more potently relaxed the contractions induced by phenylephrine (10–5 M) than those by high K+ (75 mM). KMUP 880708‐induced relaxation was significantly reduced by endothelium removal and by exposure to L‐NG‐nitro arginine methyl ester (L‐NAME, 1 and 3 × 10–4 M), indomethacin (3 × 10–5 M), methylene blue (10–5 M) and 1H‐[1,2,4]oxadiazolol[4,3,‐a]quinoxalin‐1‐one (ODQ, 10–6 M). The vasorelaxant effect of KMUP 880708 on phenylephrine‐induced contraction was attenuated by the pretreatment with tetraethylammonium (TEA), glibenclamide, charybdotoxin, and apamin, but not by 4‐aminopyridine (4‐AP). In addition, KMUP 880708 inhibited phenylephrine‐induced biphasic contraction and affected the fast‐twitch phase more significantly than the slow tonic phase. In the radioligand‐binding assay, the Ki values of [3H]CGP‐12177 binding to rat ventricle and lung membranes were 15.14 and 524.81 nM, respectively, and the value of [3H]prazosin binding to rat brain membrane was 3.89 nM. The ranking order of inhibition for [3H]CGP‐12177 binding on β‐adrenoceptor was propranolol > labetalol > KMUP 880708 > atenolol, and that for [3H]prazosin binding to α‐adrenoceptor was KMUP 880708 > labetalol. In conclusion, KMUP 880708 was found to be a new generation α/β‐adrenoceptor blocker with selective β1‐adrenoceptor blocking and vascular smooth muscle relaxation activities. Furthermore, the vasodilator effect of KMUP 880708 is attributed to the release of NO or NO‐related substance from vascular endothelium. While the endothelium‐independent mechanism involved in the relaxation of KMUP 880708 is probably linked to K+ channel activation in these vessels. Drug Dev. Res. 55:104–117, 2002. © 2002 Wiley‐Liss, Inc. 相似文献
19.
Jixia Yang Gongzheng Zhang Zhaoyang Wang Zhanxiong Xiao Hongliang Wen 《Journal of labelled compounds & radiopharmaceuticals》2019,62(14):920-924
Parkinson disease (PD) is a neurodegenerative disorder characterized by the accumulation of α‐synuclein into Lewy bodies. 3‐Benzylidine‐indolin‐2‐one represents a class of compounds, which are known to inhibit the accumulation of α‐synuclein. In this paper, we report the synthesis of [13C] and [15N] labelled 1‐benzyl‐(Z)‐3‐(benzylidene)indolin‐2‐one from commercially available [13C2]‐chloroacetic acid and [15N]‐aniline in five steps. The product will be used to study its metabolites in human liver microsomes by liquid chromatography‐tandem mass spectrometry. 相似文献
20.
M. Anissimova L. Yaouancq M.‐A. Badet‐Denisot B. Badet 《Chemical biology & drug design》2003,62(2):88-95
Abstract: A direct continuous UV–Vis spectrophotometric assay has been developed for VanX, a d ‐alanyl‐d ‐alanine aminodipeptidase necessary for vancomycin resistance. This method is based on the hydrolysis of the alternative substrate d ‐alanyl‐α‐(R)‐phenylthio‐glycine d ‐Ala‐d ‐Gly(S‐Ph)‐OH (H‐d Ala‐d Psg‐OH, 5a ). Spontaneous decomposition of the released phenylthioglycine generates thiophenol, which is quantified using Ellman's reagent. The dipeptide behaved as an excellent substrate of VanX, exhibiting Michaelis–Menten kinetics with a kcat of 76 ± 5/s and a KM of 0.83 ± 0.08 mm (kcat = 46 ± 3/s and KM = 0.11 ± 0.01 mm for d ‐Ala‐d ‐Ala). Determination of the kinetic parameters of the previously reported mechanism‐based inhibitor d ‐Ala‐d ‐Gly(SΦp‐CHF2)‐OH (H‐d ‐Ala‐d Pfg‐OH, 5c ) [Araoz, R., Anhalt, E., René, L., Badet‐Denisot, M.‐A., Courvalin, P. & Badet, B. (2000) Biochemistry 39, 15971–15979] using the substrate reported in the present study yielded values of Kirr of 22 ± 1 μm and kinact of 9.3 ± 0.4/min in good agreement with values previously obtained in our laboratory (Kirr = 30 ± 1 mm ; kinact = 7.3 ± 0.3/min). In addition, inhibition by the competing substrate d ‐Ala‐d ‐Ala resulted in determination of a Ki = 70 ± 6 μm close to the previously reported KM value. These results demonstrate that the present assay is a convenient, rapid and sensitive tool in the search for VanX inhibitors. 相似文献