Abstract:
:Ligand-receptor binding kinetics (i.e. association and dissociation rates) are emerging as important parameters for drug efficacy in vivo. Awareness of the kinetic behavior of endogenous ligands is pivotal, as drugs often have to compete with those. The binding kinetics of neurokinin 1 (NK1) receptor antagonists have been widely investigated while binding kinetics of endogenous tachykinins have hardly been reported, if at all. Therefore, the aim of this research was to investigate the binding kinetics of endogenous tachykinins and derivatives thereof and their role in the activation of the NK1 receptor. We determined the binding kinetics of seven tachykinins targeting the NK1 receptor. Dissociation rate constants (koff) ranged from 0.026±0.0029min-1 (Sar9,Met(O2)11-SP) to 0.21±0.015min-1 (septide). Association rate constants (kon) were more diverse: substance P (SP) associated the fastest with a kon value of 0.24±0.046nM-1min-1 while neurokinin A (NKA) had the slowest association rate constant of 0.001±0.0002nM-1min-1. Kinetic binding parameters were highly correlated with potency and maximal response values determined in label-free impedance-based experiments on U-251 MG cells. Our research demonstrates large variations in binding kinetics of tachykinins which correlate to receptor activation. These findings provide new insights into the ligand-receptor interactions of tachykinins and underline the importance of measuring binding kinetics of both drug candidates and competing endogenous ligands.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Nederpelt I,Bleeker D,Tuijt B,IJzerman AP,Heitman LHdoi
10.1016/j.bcp.2016.08.004subject
Has Abstractpub_date
2016-10-15 00:00:00pages
88-95eissn
0006-2952issn
1873-2968pii
S0006-2952(16)30221-0journal_volume
118pub_type
杂志文章abstract::The inhibitory effects of N-(4-hydroxyphenyl)retinamide (HPR) and its glucuronide derivative on the growth of MCF-7 human breast cancer cells in vitro were compared. The results indicate that the glucuronide had slightly greater potency and much less cytotoxicity than the free retinoid. At a concentration of 10(-6) M,...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90563-k
更新日期:1991-05-15 00:00:00
abstract::The protein tyrosine kinase (PTK) inhibitor genistein has been demonstrated to inhibit platelet-activating factor-stimulated prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-primed P388D1 macrophage-like cells (Glaser et al., J Biol Chem 265: 8658-8664, 1990). Therefore, the role of PTK in eicosanoid bio...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90147-o
更新日期:1993-02-09 00:00:00
abstract::Magnesium-pyridoxal-5'-phosphate-glutamate (MPPG) has been shown to ameliorate atherosclerotic symptoms in rabbits. In vitro, MPPG in the presence of peroxides such as cholesterolhydroperoxide or cumene hydroperoxide and Mn2+ ions produces "excited states" measurable as chemiluminescence or ethylene release from 1-ami...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(92)90442-l
更新日期:1992-08-04 00:00:00
abstract::It is believed that chemotherapeutic agents can enhance the malignancy of treated cancer cells in clinical situations, which is a major problem for chemotherapy. However, the underlying molecular mechanisms are still not fully understood. Here, we demonstrated that chemotherapy up-regulates the levels of spermatogenic...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2018.07.046
更新日期:2018-10-01 00:00:00
abstract::The cytoprotective effects of propylthiouracil (PTU) were studied in rats treated with the hepatotoxin D-galactosamine (D-GNH2). Five days of PTU pretreatment prior to D-GNH2 caused hypothyroidism and a significant reduction in liver injury as assessed by serum transaminase levels. When PTU was administered as a singl...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(84)90110-2
更新日期:1984-11-01 00:00:00
abstract::It has been reported that an extract from Angelica sinensis mainly consisting of polysaccharides (95%) prevented ethanol- or indomethacin-induced gastric mucosal damage (Cho CH et al. Planta Med 2000;66:348-51). However, it is not known whether Angelica sinensis has a direct stimulatory effect on the healing of gastri...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(01)00625-6
更新日期:2001-06-01 00:00:00
abstract::The present study addressed the question of whether the number of myocardial beta-adrenoceptors in rats with 4- to 6-week streptozotocin-induced diabetes is regulated in a transcriptional or translational manner. Radioligand binding experiments with [3H]CGP 12177 {4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H]benzimidaz...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(99)00164-1
更新日期:1999-09-01 00:00:00
abstract::Flunarizine, a calcium (Ca2+)-entry blocker, selective for vascular tissues, inhibits in a concn-dependent way the contraction of isolated rat caudal artery preparations induced by mediators derived from thrombin-stimulated rat platelets. This inhibition is slow in onset and is of prolonged duration. Specific measurem...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(83)90574-9
更新日期:1983-03-01 00:00:00
abstract::Triapine is an α-N-heterocyclic thiosemicarbazone with promising anticancer activity against hematologic malignancies but widely ineffective against solid tumor types in clinical trials. The anticancer activity of thiosemicarbazones can be dramatically increased by terminal dimethylation. KP1089 is a gallium compound ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2012.03.004
更新日期:2012-06-15 00:00:00
abstract::A novel enzyme that converts dihydroxyphenylacetic acid (DOPAC) to dihydroxyphenylethanol (DOPET) was found to be present in the microdialysate of the rat brain. The enzyme, named DOPAC reductase, was inhibited by EDTA and stimulated by divalent cations like Zn2+, Mn2+, Co2+ and Cu2+. Its Km, pH optimum and temperatur...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(95)02092-6
更新日期:1995-10-26 00:00:00
abstract::An important pathologic hallmark of Alzheimer's disease (AD) is neuroinflammation, a process characterized in AD by disproportionate activation of cells (microglia and astrocytes, primarily) of the non-specific innate immune system within the CNS. While inflammation itself is not intrinsically detrimental, a delicate ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2013.12.014
更新日期:2014-04-15 00:00:00
abstract::The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox-sensitive transcription factors such as nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), which regulate the genes for proinflammatory mediators and protective antioxidant genes. GSH, a ubiquitous tripeptide t...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/s0006-2952(00)00392-0
更新日期:2000-10-15 00:00:00
abstract::The salt-induced condensation of chromatin has been studied with flow-linear dichroism technique using an intercalative dye (methylene blue) to selectively monitor the linker orientation. At low ionic strength both linkers and chromatosomes (with their flat faces) are oriented preferentially parallel to the chromatin ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(88)90459-5
更新日期:1988-05-01 00:00:00
abstract::The glycolipid alpha-galactosylceramide (alpha-GalCer), when presented on CD1 molecules by antigen presenting cells (APCs) to invariant NKT (iNKT cells), is a potent immunomodulator. Indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing the catabolism of L-tryptophan along the kynurenine pathway, is inducible in APC...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2008.07.001
更新日期:2008-09-15 00:00:00
abstract::Metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone, MTP) is used as an inhibitor of cytochrome P-450 enzymes, particularly those induced by phenobarbital (PB). We examined the effects of MTP on the microsomal dependent mutagenesis of a newly isolated promutagen, 3-(2-chloroethoxy)-1,2-dichloropropene (CP), three S-chlo...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(83)90144-2
更新日期:1983-12-15 00:00:00
abstract::Heme oxygenase 1 (HO-1) is a stress protein and has been suggested to provide defense mechanisms against agents that may induce oxidative injury. Vitamin E (VE) is considered to function as an important cellular antioxidant. Rats were fed a VE-deficient (0E) or a VE-sufficient (10E) diet for 6 weeks and then were intr...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(97)00302-x
更新日期:1997-11-15 00:00:00
abstract::Porcine cerebral microvessels were isolated by differential sieving and centrifugation and were characterized by microscopic examination and marker enzyme enrichment (gamma-glutamyltransferase; EC 2.3.2.2). Purified microvessels contained a membrane-bound enzyme immunologically indistinguishable from renal aminopeptid...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(88)90712-5
更新日期:1988-01-15 00:00:00
abstract::A serine peptidase (RLK1) was partially purified from rat liver homogenates. Its molecular weight was 80,000, and its optimum pH was 7.5. Bz-Tyr-O-Et was hydrolyzed by the enzyme, which was inhibited by Ip2PF, PMSF and by Tos-Phe-CH2Cl. The bonds cleaved by the enzyme were Phe5-Ser6 and Phe8-Arg9, when bradykinin was ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90466-x
更新日期:1982-03-01 00:00:00
abstract::MRS 1754 [N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide] is a selective antagonist ligand of A(2B) adenosine receptors. This is the least well-defined adenosine receptor subtype, and A(2B) antagonists have potential as antiasthmatic drugs. For use as a radioligand, ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(01)00531-7
更新日期:2001-03-15 00:00:00
abstract::CYP3A4 is the most important drug-metabolizing enzyme that is involved in biotransformation of more than 50% of drugs. Pregnane X receptor (PXR) dominantly controls CYP3A4 inducibility in the liver, whereas vitamin D receptor (VDR) transactivates CYP3A4 in the intestine by secondary bile acids. Four major functional P...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.08.017
更新日期:2010-01-15 00:00:00
abstract::Amodiaquine, a 4-aminoquinoline antimalarial, has been associated with hepatitis and agranulocytosis in humans. Drug hypersensitivity reactions, especially agranulocytosis, have been attributed to reactive intermediates generated by the oxidants discharged from stimulated polymorphonuclear leucocytes (PMN). The metabo...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(95)00236-s
更新日期:1995-09-28 00:00:00
abstract::The calcium-ionophore A23187 causes a reversible increase of the hydrostatic pressure in the portal vein of perfused rat liver. Concomitantly, hepatic functions like the production of bile and the transhepatic movement of the bile acid taurocholate are diminished, mainly due to decreased uptake. These phenomena are pa...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(87)90221-8
更新日期:1987-09-15 00:00:00
abstract::Tachykinin NK receptors (NKRs) differ to a large degree among species with respect to their affinities for small molecule antagonists. The aims of the present study were to clone NKRs from gerbil (NK2R and NK3R) and dog (NK1R, NK2R and NK3R) in which the sequence was previously unknown and to investigate the potency o...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.01.020
更新日期:2009-05-01 00:00:00
abstract::The human platelet thromboxane A2/prostaglandin H2 receptor has been purified 6100-fold to apparent homogeneity by a three-step chromatographic procedure with an overall yield of 6%. A 6-fold purification of the receptor was first achieved by chromatography of 3-[(3-cholamidopropyl)dimethyl-ammonio]-1-propanesulfonate...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(92)90294-s
更新日期:1992-01-22 00:00:00
abstract::Prostacyclin and beraprost sodium (beraprost), a stable analogue of prostacyclin, increased cyclic AMP (cAMP) levels of cultured human umbilical vein endothelial cells (HUVEC) in a concentration-dependent manner. The elevation of cAMP by beraprost was sustained longer than that by prostacyclin. The expression of throm...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90651-k
更新日期:1991-04-15 00:00:00
abstract::We previously reported that in hyperuricemic rats, renal impairment occurred and organic ion transport activity decreased, accompanied with a specific decrease in the expression of rat organic anion transporters, rOAT1 and rOAT3, and organic cation transporter, rOCT2. In the present study, we investigated the reversib...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2004.12.004
更新日期:2005-03-15 00:00:00
abstract::Desipramine (DMI) is an important antidepressant drug and a lysosomotropic substance. In cultured fibroblasts it interferes with lysosomal functions, e.g. phospholipid degradation. Chronic exposure of cells with DMI induces storage of phospholipids. Subcellular fractionations of cultured human fibroblasts that had bee...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(87)90716-7
更新日期:1987-03-01 00:00:00
abstract::Inflammation is a multi-staged process whose expansive phase is thought to be driven by acutely released arachidonic acid (AA) and its metabolites. Inhibition of cyclooxygenase (COX), lipoxygenase (LOX), or soluble epoxide hydrolase (sEH) is known to be anti-inflammatory. Inhibition of sEH stabilizes the cytochrome P4...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.10.025
更新日期:2010-03-15 00:00:00
abstract::The binding of 1,1-dichloroethane (1,1-DCE) to the substrate binding site of hepatic microsomal cytochrome P-450, and the stimulation of hepatic microsomal CO-inhibitable NADPH oxidation by 1,1-DCE and 1,2-dichloroethane (1,2-DCE) were enhanced by induction with phenobarbital but not with beta-naphthoflavone. Incubati...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(83)90545-2
更新日期:1983-01-15 00:00:00
abstract::Clonidine-displacing substance (CDS) from brain is biologically active in the kidney and stomach and on platelets. To determine whether CDS is contained in these and other peripheral tissues, homogenates of fresh brain, eight other organs and serum from rat were ultrafiltered (less than 10,000 mol. wt only), dried and...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(92)90410-k
更新日期:1992-08-18 00:00:00