Abstract:
:The loss of cholinergic neurons and synapses relates to the severity of dementia in several neurodegenerative pathologies; and the vesicular acetylcholine transporter (VAChT) provides a reliable biomarker of cholinergic function. We recently characterized and (11)C-labeled a new VAChT inhibitor, (-)-TZ659. Here we report the in vitro and ex vivo characterization of (-)-TZ659. A stably transfected PC12(A123.7) cell line which expresses human VAChT (hVAChT) was used for the in vitro binding characterization of (-)-[(3)H]TZ659. A saturated binding curve was obtained with Kd=1.97±0.30nM and Bmax=3240±145.9fmol/mg protein. In comparison, a PC12(A123.7) cell line that expresses mutant hVAChT showed decreased binding affinity (Kd=15.94±0.28nM). Competitive binding assays using a panel of other CNS ligands showed no inhibition of (-)-[(3)H]TZ659 binding. On the other hand, binding inhibitions were observed only using VAChT inhibitors (Ki=0.20-31.35nM). An in vitro assay using rat brain homogenates showed that (-)-[(3)H]TZ659 had higher binding in striatum than in cerebellum, with a target: non-target ratio>3.46. Even higher ex vivo striatum-to-cerebellum ratios (9.56±1.11) were observed using filtered homogenates of brain tissue after rats were injected intravenously with (-)-[(11)C]TZ659. Ex vivo autoradiography of (-)-[(11)C]TZ659 confirmed high striatal uptake, with a consistently high striatum-to-cerebellum ratio (2.99±0.44). In conclusion, (-)-TZ659 demonstrated high potency and good specificity for VAChT in vitro and in vivo. These data suggest that (-)-[(11)C]TZ659 may be a promising PET tracer to image VAChT in the brain.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Liu H,Jin H,Li J,Zhang X,Kaneshige K,Parsons SM,Perlmutter JS,Tu Zdoi
10.1016/j.ejphar.2015.02.001subject
Has Abstractpub_date
2015-04-05 00:00:00pages
18-25eissn
0014-2999issn
1879-0712pii
S0014-2999(15)00081-3journal_volume
752pub_type
杂志文章abstract::In this study, we describe the effect of antiepileptic drugs on the production of kynurenic acid in rat cortical slices, and on the activity of kynurenic acid biosynthetic enzymes, kynurenine aminotransferases (KATs I and II) in the brain tissue. Phenobarbital, felbamate, phenytoin and lamotrigine (all at 0.5-3.0 mM) ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2006.05.015
更新日期:2006-07-17 00:00:00
abstract::Endo/sarcoplasmic reticulum stress and the unfolded protein response have been implicated as underlying mechanisms of cell death in many pathological conditions. We have confirmed that long-term exposure to 10µM tunicamycin induced the endo/sarcoplasmic reticulum stress in cultured vascular smooth muscle cells. Since ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2014.04.025
更新日期:2014-07-15 00:00:00
abstract::Little research has been conducted investigating the long-term impact of opioid exposure during adolescence. These experiments were conducted to determine the behavioral effects of morphine exposure during periadolescence (postnatal days 30-32) versus young adulthood (postnatal days 65-67) on subsequent sensitivity to...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2005.10.026
更新日期:2005-12-28 00:00:00
abstract::Apoptosis has received widespread attention for its essential roles in biology, medicine and cancer. We previously found that normal, human papillomavirus (HPV) 16-immortalized and their transformed endocervical cells were increasingly resistant to apoptosis induced by a cancer therapeutic drug. Here, analogously, ano...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(03)01561-9
更新日期:2003-04-25 00:00:00
abstract::An antagonist of morphine analgesia, N-cyclopropylmethylnorazidomorphine (CAM) inhibited the"wet shakes" appearing during spontaneous or nalorphine-precipitated morphine abstinence. CAM inhibited the pinna reflex more strongly than did morphine and selectively antagonized quipazine-induced head twitches; its inhibitio...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(78)90358-8
更新日期:1978-08-01 00:00:00
abstract::Hypoxia-inducible factor prolyl hydroxylases (PHDs) inhibitor stabilizes hypoxia inducible factor alpha, which increases erythropoietin (EPO) expression via the hypoxia response element. Therefore, PHDs inhibitors have been developed as novel therapeutic agents for anemia. Here, we characterize the in vitro and in viv...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2018.08.044
更新日期:2018-11-05 00:00:00
abstract::Vancomycin (VCM) is a first-line antibiotic for serious infections caused by methicillin-resistant Staphylococcus aureus. However, nephrotoxicity is one of the most complaint in VCM therapy. We previously reported that VCM induced apoptosis in a porcine proximal tubular epithelial cell line (LLC-PK1), in which mitocho...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2017.02.025
更新日期:2017-04-05 00:00:00
abstract::In the present study, we investigated whether copper ions are involved in the decomposition of endogenous S-nitrosothiols by ultraviolet (UV) light irradiation in the mouse gastric fundus. The effects of copper ions and chelators of copper(I) and copper(II), neocuproine and cuprozine, respectively, were studied on rel...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2003.11.036
更新日期:2004-02-06 00:00:00
abstract::The potential of resiniferatoxin and capsaicin to modulate emesis and genital grooming was investigated in Suncus murinus. Resinifertoxin (3-30 nmol, i.c.v.), E-capsaicin (10-100 nmol, i.c.v.) and Z-capsaicin (100 nmol, i.c.v.) induced emesis (P<0.05) and subsequently antagonised the emetic response induced by intraga...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(01)01041-x
更新日期:2001-06-22 00:00:00
abstract::The chick has a practical advantage in the screening process in that chicks require only small quantities of drugs. The chick separation stress paradigm has traditionally been recognized as a valid form of anxiolytic screening. Further, chick behavior involving standing motionless with eyes closed or sitting motionles...
journal_title:European journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.ejphar.2015.06.036
更新日期:2015-09-05 00:00:00
abstract::Numerous studies have demonstrated the stimulatory effect of 5-HT1A receptor agonists, such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on plasma corticotrophin (ACTH) levels in the rat. However, until recently the lack of a selective 5-HT1A receptor antagonist has hampered mechanistic studies in this area....
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(94)90642-4
更新日期:1994-10-13 00:00:00
abstract::Ketamine, a non-selective inhibitor of NMDA (N-methyl-D-aspartate) channels is used in anesthetic or sub-anesthetic doses to induce analgesia, amnesia, to suppress fear, anxiety and depression. Although the ketamine's effect on memory acquisition is known, its effects on other aspects of memory are controversial. Morr...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2011.12.021
更新日期:2012-02-29 00:00:00
abstract::Morphine-induced analgesia, and the development of morphine-induced tolerance and dependence was determined in mice which had drunk caffeinated water (1 mg/ml) for 14 days or in mice which had received (-)-N6-(phenylisopropyl)-adenosine (PIA) 1 mg/kg i.p. for 14 days. Analgesia was assessed by the tail flick assay. Th...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(86)90635-7
更新日期:1986-01-14 00:00:00
abstract::It has been reported that the antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) may result from the modulation of brain monoaminergic systems. However, the mechanisms of FDPI action are not fully understood. The aim of this study was to investigate the contribution of N-methyl-d-aspartate ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2016.04.046
更新日期:2016-07-05 00:00:00
abstract::Hyperphosphatemia is associated with severe decline of renal function in chronic kidney disease and elevates cardiovascular mortality. Type II sodium dependent phosphate transporter 2A (Npt2A) plays a major role in renal phosphate reabsorption and could be explored as a target for anti-hyperphosphatemia therapy. Human...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2013.09.005
更新日期:2013-12-05 00:00:00
abstract::Recombinant human GABA(A) receptors were investigated in vitro by coexpression of cDNAs coding for alpha1, beta2, and gamma2 subunits in the baculovirus/Sf-9 insect cell system. We report that a single amino acid exchange (isoleucine 121 to valine 121) in the N-terminal, extracellular part of the alpha1 subunit induce...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:
更新日期:1997-06-25 00:00:00
abstract::PCA 50941 is a novel 1,4-dihydropyridine derivative. Its vasoconstricting effects prompted a systematic comparison with the prototypic Ca2+ channel activator, Bay K 8644. The two compounds exhibit marked analogies and differences in their cardiovascular profiles. PCA 50941 exhibits a pronounced vascular over cardiac s...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(93)90163-c
更新日期:1993-10-12 00:00:00
abstract::The effects of Ca2+ channel antagonists on the capsaicin-induced cough reflex in guinea pigs were studied. Intraperitoneal injection of nifedipine, verapamil and flunarizine in doses that ranged from 0.3 to 3.0 mg/kg decreased the number of coughs in a dose-dependent manner. These Ca2+ channel antagonists exhibited an...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(92)90072-c
更新日期:1992-02-25 00:00:00
abstract::Systemic administration of the NMDA receptor antagonist phencyclidine (PCP; 4 mg/kg) produced a profound reduction in prepulse inhibition of the acoustic startle response in rats. Pre-treatment with the selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) blocked (0.5 mg/kg) or attenuated (0.1 and 0.2...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(99)00088-6
更新日期:1999-03-26 00:00:00
abstract::The action of organic solvents on the biochemical and biophysical properties of protein kinase C (PKC) was measured in a defined lipid vesicle system. Chloroform, benzyl alcohol and ethanol all partially activated PKC. They had no effect on the Ca(2+)- or anionic phospholipid-, phosphatidylserine-dependence. Their abi...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0922-4106(91)90114-w
更新日期:1991-04-25 00:00:00
abstract::We hypothesized that uncompetitive NMDA glutamate receptor antagonists memantine (2,5-dimethyl-1-adamantanamine), and amino-alkyl-cyclohexane compounds: MRZ 2/579 (1-amino-1,3,3,5,5-pentamethylcyclohexane HCl), MRZ 2/600 (1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane HCl), and MRZ 2/615 (1-amino-1,3,5,5-tetramethyl-3...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(02)02121-0
更新日期:2002-09-27 00:00:00
abstract::Acute noise stress decreased [3H]5-hydroxytryptamine ([3H]5-HT) uptake in synaptosomes from rat hypothalamus, hippocampus and cerebral cortex. The decrease was due to the maximum rate of [3H]5-HT uptake, which peaked 30 min after stress and partly returned to resting values within 4 h, with no changes in affinity (Km ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(93)90211-y
更新日期:1993-09-14 00:00:00
abstract::In the guinea-pig ileum, both sarafotoxin S6c and IRL1620 (Suc-[Glu9,Ala11,15]endothelin-1-(8-21) induced a concentration-dependent biphasic effect (relaxation and contraction), but distinct tachyphylaxis of the tissue. Cross-tachyphylaxis and additivity experiments evidenced distinct receptors for these agonists. BQ-...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(99)00062-x
更新日期:1999-03-19 00:00:00
abstract::Amitriptyline is known to increase the permeability of the blood-brain barrier but the morphological basis of this increase has not been studied. As catecholamines can influence pinocytosis in dog peripheral blood vessels, the effect of amitriptyline on the pinocytotic activity of blood brain microvessels was studied....
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(90)90133-q
更新日期:1990-01-25 00:00:00
abstract::Quantitative receptor autoradiography has been employed to determine the binding distribution of [3H]SR 95531 (2'-(3'-carboxy-2',3'-propyl)-3-amino-6-p-methoxyphenylpyrazinium bromide), a GABAA receptor antagonist, in the rat brain. The location showed good correspondence, in most areas, with the binding of [3H]GABA t...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(88)90576-6
更新日期:1988-03-29 00:00:00
abstract::(-)-3/-Norepinephrine (3H-NE) binding to the microsomal fraction of the rabbit aorta has been studied. Binding appears to increase linearly with time up to at least 30 min, shows no evidence of stereoselectivity and may be inhibited only by compounds possessing the catechol or 3-methoxy-4hydroxyphenyl moieties, with t...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(76)90324-1
更新日期:1976-08-01 00:00:00
abstract::Adriamycin-induced nephrosis in rats is a commonly used experimental model for pharmacological studies of human chronic renal diseases. Adriamycin-induced apoptosis of renal tubular cells has been reported in adriamycin-treated rats. In addition, prostacyclin (PGI(2)) is known to have various protective effects on man...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2005.10.057
更新日期:2006-01-04 00:00:00
abstract::Pregnant rats were infused with phentermine plus dexfenfluramine from days 3 through 17 of gestation. Control rats were either pair-fed or were fed ad libitum. There were no effects of prenatal drug treatment on number of offspring, their birth weights, or on their motor coordination assessed at 11 days of age. Mother...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(99)00100-4
更新日期:1999-03-26 00:00:00
abstract::Intracellular recordings were made from myenteric neurons of the guinea-pig duodenum and the responses to local ejection of several substance P (SP) analogs were examined. It was found that senktide (succinyl-[Asp6,Me-Phe8]SP-(6-11)), a selective analog for the NK-3 (SP-N) receptor, was particularly effective in depol...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(88)90612-7
更新日期:1988-08-24 00:00:00
abstract::Oxyntomodulin, a hormone released from jejuno-ileum and composed of the glucagon sequence extended by a C-terminal octapeptide displays original tissue specificity for the gastric mucosa. The aim of this study was to compare the effect of oxyntomodulin on histamine (0.4 mg/kg per h)-stimulated gastric acid secretion i...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(91)90720-b
更新日期:1991-10-15 00:00:00