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61.
H. Glossmann P. Presek E. Eigenbrodt 《Naunyn-Schmiedeberg's archives of pharmacology》1981,317(1):100-102
Summary The bioflavonoid quercetin is a potent inhibitor of a cyclic nucleotide-independent, tumor virus-coded protein kinase which phosphorylates tyrosine residues and acts as a cellular transforming protein. Half-maximal inhibition of the protein kinase occurred at 3–4 M quercetin whereas rutin was much less effective. The finding, that quercetin inhibits a cyclic nucleotide-independent protein kinase activity, may provide clues to the diverse pharmacological effects of the bioflavonoids. 相似文献
62.
In Madin Darby canine kidney (MDCK) cells epinephrine--via alpha-adrenoceptors--leads to sustained hyperpolarization of the cell membrane. The present study defined the subtype of alpha-adrenoceptor involved. Both the alpha 1-adrenoceptor agonist, phenylephrine, and alpha 2-adrenoceptor agonists (BHT 920, guanfacine, moxonidine, oximetazoline) were able to hyperpolarize the cell membrane. The effect of epinephrine was only transient in the presence of the alpha 2-adrenoceptor antagonist, yohimbine, whereas the effect persisted in the presence of the alpha 1-adrenoceptor antagonist, prazosin. The epinephrine-induced hyperpolarization was almost abolished in the presence of both prazosin and yohimbine. In conclusion, both, alpha 1- and alpha 2-receptors are involved in the hyperpolarizing action of epinephrine. 相似文献
63.
H. Glossmann 《Naunyn-Schmiedeberg's archives of pharmacology》1975,289(1):99-109
Summary Speci fic binding sites for 5-guanylyl-imidodiphosphate [Gpp(NH)p] have been identified in a partially purified plasma membrane fraction from bovine adrenal cortex. The apparent affinity of Gpp(NH)p at 30° C was 12 M–1 and the concentration of binding sites was 100 pmoles per mg of protein. Binding of Gpp (NH)p is inhibited by Mn2+ > Mg2+ Ca2+ and enhanced by low concentrations of the chelators ethylenediamino-tetraacetic acid (EDTA) and ethylene glycolbis-(-aminoethylether)-N,N'-tetraacetic acid (EGTA). High concentrations of EDTA are inhibitory and at 2.5 mM EDTA binding of Gpp(NH)p is only 10% of that observed in the absence of the chelator. The bound labeled GTP analogue exchanged only slowly with the unlabeled nucleotide after a steady state has been reached. EDTA also releases the bound labeled Gpp(NH)p from its binding sites. The slow dissociation of Gpp(NH)p can explain the persistent activation of adenylate cyclase observed after pretreatment of bovine adrenal cortex plasma membranes with Gpp(NH)p and subsequent washing.It is suggested that at least parts of these binding sites are identical to the sites identified earlier as regulatory sites for angiotensin high-affinity receptors (Glossmann et al., 1974a) and for ACTH-stimulated cyclase (Glossmann and Gips, 1974). 相似文献
64.
Alfred Grassegger Jörg Striessnig Markus Weiler Hans-Günther Knaus Hartmut Glossmann 《Naunyn-Schmiedeberg's archives of pharmacology》1989,340(6):752-759
Summary Benzothiazinones represent a novel class of drugs which block voltage-dependent L-type calcium channels in different tissues. [3H]HOE166 (R-(±)-3,4-dihydro-2-isopro-opyl-4-methyl-2-[2-[4-[4-[2-(3, 4, 5-trimethoxyphenyl)ethyl]piperazinyl]butoxy]phenyl]-2H -1, 4-benzothiazin-3-on-dihydrochloride; 57 Ci/mmol) a potent optically pure benzothiazinone was employed to characterize receptors associated with skeletal muscle transverse tubule calcium channels. [3H]HOE166 reversibly labels the membrane-bound calcium channels with high affinity (Kd = 0.36 ± 0.05 nM; Bmax = 18.2 ± 3.3 pmol/mg of membrane protein; means ± SD, n = 13), HOE166 (Ki = 0.76 nM) is 29-fold more potent than the respective (S)-enantiomer (Ki = 22.1 nM). Binding is inhibited by divalent and trivalent cations (Cd2+ and La3+ being most potent) and other calcium channel drugs (1,4 dihydropyridines, phenylalkylamines, benzothiazepines). High affinity [3H]HOE166 binding activity is maintained (Kd = 4.5–9.0 nM) after solubilization and purification (554–1350 pmoles/mg of protein) of the calcium channel complex from transverse-tubule membranes. The following data support our recent claim (Striessnig et al. 1985, 1988) that HOE166 labels a domain on L-type calcium channels which is distinct from that defined by 1,4 dihydropyridines, phenylalkylamines or benzothiazepines: (1) All 1,4 dihydropyridine-, phenylalkylamine-and benzothiazepine-receptor-selective drugs tested are only very weak inhibitors of [3H]HOE166 binding. (2) (+)-PN200-110 only partially inhibits [3H]HOE166 binding to the purified calcium. channel complex. (3) The decay of the [3H]HOE166-receptor complex is monoexponential but the dissociation rate constants depend on the ligand concentration; (+)-PN200-100 accelerates the dissociation in the presence of unlabelled HOE166. (4) Nanomolar concentrations of HOE166 and HOE167 completely inhibit (–)-[3H]desmethoxyverapamil binding to a Drosophila phenylalkylamine receptor (which lacks a 1,4 dihydropyridine binding domain). Taken together, these results are incompatible with the view that [3H]HOE166 binds competitively to the calcium channel linked 1,4 dihydropyridine drug receptors.Abbreviations kd
dissociation constant
- Ki
inhibition constant
- k–1,k+1
dissociation, association rate constant
- SDS
sodium dodecyl sulfate
- T-tubule
transverse tubule
- s20,w
sedimentation coefficient
Send offprint requests to H. Glossmann at the above address 相似文献
65.
Hartmut Glossmann Friedrich Lübbecke Barbara Habermann 《Naunyn-Schmiedeberg's archives of pharmacology》1982,321(1):7-10
Summary [125I]-HEAT,125iodo-2-[-(4-hydroxyphenyl)-ethyl-aminomethyl]tetralone, is a novel alpha1-adrenoceptor ligand which labels alpha1-adrenoceptors in peripheral tissues as well as in the central nervous system. Using the technique of ligand saturation by receptors, we find that only 50% of the125I-labeled HEAT molecules bind with high affinity to receptors from a variety of tissues.This was observed with partially purified rat brain membranes and highly purified rat liver plasma membranes in the absence or presence of sodium ion (as NaCl, 150 mM) which stimulated125I-HEAT binding, by increasing the affinity. If the bindability of [125I]-HEAT is taken into account,K
D values as low as 7–8 pM (at 30°C) are found in equilibrium binding experiments and optimally stimulating concentrations of sodium ion. The limited high affinity binding of [125I]-HEAT could not be explained by radiochemical impurities. Instead, we suggest that only one enantiomer of the racemic ligand is preferentially bound to the receptors with aK
D in the picomolar range.Since the enantiomers are in dynamic equilibrium in solution (via keto-enol tautomerism) [125I]-HEAT is a unique radioligand which makes it unlikely that the respective isomers can be separated by successive depletion with receptors. 相似文献
66.
Molecular mechanisms of the effects of sildenafil (VIAGRA). 总被引:2,自引:0,他引:2
The molecular mechanisms of the effects of sildenafil, a specific inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterases are briefly reviewed. The second messenger cGMP as well as its molecular targets (with the exception of the photoreceptor signal transduction machinery) have long played an underdog role compared with cyclic adenosine monophosphate and other signalling molecules such as inositoltrisphosphate. The same holds for guanylyl cyclase, which, albeit being the main effector molecule of the gaseous neurotransmitters carbon monoxide and nitric oxide (NO), has received much less attention relative to its activators and their synthases. Stimulation of the arginine --> NO --> cGMP pathway by bypassing NO-synthase is a well-established pharmacological principle in the treatment of cardiovascular disorders. In contrast, local application of NO-donors or oral feeding of excessive amounts of precursor amino acid L-arginine to treat erectile dysfunction were met with variable success or failure. The advent of a new principle, amplification of the NO-signaling cascade by means of target organ selective phosphodiesterase inhibition, has renewed interest in phosphodiesterases and cGMP. 相似文献
67.
Prof. Dr. Bernhard J. Steinhoff Wilhelm Frenck Jan-Peter Ernst 《Zeitschrift für Epileptologie》2009,22(1):9-12
In order to investigate the five-year retention rate after initiation of add-on levetiracteam (LEV) in patients with localization-related epilepsy syndromes, we followed 90 patients after the launch of LEV in August 2000 in Germany. After five years, there were still 37 patients (41%) on LEV. In 3 patients, all AEDs were tapered since the patients were seizure free (2 of them after epilepsy surgery). Fifteen patients were still responders (17% of all patients at initiation of LEV treatment, 45% of patients still on LEV after five years), 3 of them were seizure free (8% of 37 patients still on LEV). In 2 further patients LEV is still taken, despite being seizure free after epilepsy surgery. The remaining patients continued with LEV although they were no responders. In these cases, improved vigilance and cognition occurred or AEDs that had caused tolerability problems could be withdrawn. 相似文献
68.
69.
The so-called calcium antagonist D-600 and agents that enhance the influx of calcium ions into nerve terminals during action potentials (4-aminopyridine, tetraethylammonium, guanidine) interact with alpha-adrenoceptors. The interaction was revealed by binding experiments in vitro with the alpha 2- and alpha 1-specific ligands [3H]clonidine and [3H]prazosin, resp. D-600 binds in a competitive manner to alpha 2- and alpha 1-adrenoceptors in rat-brain membranes. [3H]Prazosin was used to identify alpha 1-adrenoceptors in rat-heart-membrane fragments. D-600 inhibited the binding of the tritiated antagonist, in a manner similar to that seen in rat-brain membranes. 4-Aminopyridine, guanidine and tetraethylammonium blocked no-competitvely the binding of [3H]clonidine in brain membranes. There ws little or no effect of these agents on the binding of [3H]prazosin to alpha 1-adrenoceptors in rat heart or brain. The results indicate that D-600 binds to a region common to alpha 1- and alpha 2-adrenoceptors, whereas the potassium-channel blockers reveal a structural feature of the alpha 2-adrenoceptors in brain membranes which is also present in voltage-dependent potassium channels but is not shared by alpha 1-adrenoceptors. 相似文献
70.