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21.
Mark Andrews Alan Brown Jean-Yves Chiva David Fradet David Gordon Mark Lansdell Malcolm MacKenny 《Bioorganic & medicinal chemistry letters》2009,19(8):2329-2332
The reported selective serotonin Re-uptake Inhibitor Litoxetine was used as the starting point in the design of a range of potential SSRIs with high ease of synthetic accessibility. Preparation and subsequent optimization yielded a range of potent and highly selective SSRIs. 相似文献
22.
R Shapley J Gordon 《Proceedings of the Royal Society of London. Series B, Containing papers of a Biological character. Royal Society (Great Britain)》1980,209(1175):317-330
We measured the visual sensitivity of the conger eel retina by means of its electroretinogram (e.r.g.) and whole nerve responses. The spectral sensitivity of the retina closely corresponded to a prediction based on the density spectrum of the conger visual pigment, measured in situ. The pigment density in the conger eel retina is high, perhaps as high as 1.0. Thus, the predicted spectral sensitivity would be much broader than is observed if the absorption spectrum of the pigment governed the visual sensitivity. The reason why the visual spectral sensitivity corresponds to the density spectrum and not to the absorption spectrum is that the photoreceptors in the conger eye are arranged in tiers and only the inner tier contributes to vision. 相似文献
23.
Administration of high-dose Antide to ovariectomized monkeys results in rapid, prolonged, and reversible inhibition of gonadotropin secretion. The present study examined whether similar long-term control would be manifested in the menstrual cycle of intact primates. Antide administration at a dose of either 3.0 or 18.0 mg/kg induced rapid suppression of bioassayable LH concentrations, precipitating a concurrent fall in serum progesterone concentrations from 7.9 +/- 3.6 and 5.8 +/- 1.0 ng/ml (mean +/- SEM) on the day of injection to 0.6 +/- 0.2 and 0.5 +/- 0.1 ng/ml by 2 days post-treatment, respectively. This Antide-induced luteolysis was accompanied by the premature onset of menses within 3 days. The next menses following Antide administration was delayed. Ultimately, folliculogenesis culminating in normal follicular-phase estradiol production, ovulation, and subsequent normal luteal-phase progesterone production did occur in all treated monkeys. Menses resumed 54 +/- 9 and 75 +/- 13 days after treatment with 3.0 and 18.0 mg/kg Antide, respectively. No allergic cutaneous or peripheral reactions were seen, even at the highest dose of Antide. Thus, the long duration of action of high-dose Antide reported earlier in ovariectomized monkeys is also demonstrated in intact primates. These findings, along with the apparent absence of histamine-release effects even at high doses, suggest that Antide is a GnRH antagonist deserving clinical evaluation. 相似文献
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25.
Opioids and central baroreflex control: a site of action in the nucleus tractus solitarius 总被引:1,自引:0,他引:1
F J Gordon 《Peptides》1990,11(2):305-309
These studies investigated whether the nucleus of the tractus solitarius (NTS) is a central site where opioids modulate baroreceptor reflexes. Microinjections into the NTS of [D-Ala2,MePhe4, Gly-ol5]enkephalin (DAGO) significantly reduced reflex-mediated depressor responses evoked by electrical stimulation of the aortic nerve. Subsequent NTS injections of naloxone restored baroreflexes to control levels. These results demonstrate that the NTS is a central site where exogenously administered opioids can modulate baroreceptor reflexes. NTS injections of naloxone had no effect on baroreflex function, suggesting that tonic activation of opioid receptors at this site plays little or no role in central baroreflex control. 相似文献
26.
27.
Gordon Tollin 《Journal of bioenergetics and biomembranes》1995,27(3):303-309
Photoexcitation of flavin analogs generates the lowest triplet state (via intersystem crossing from the first excited singlet state) in the nanosecond time domain and with high quantum efficiency. The triplet, being a strong oxidant, can abstract a hydrogen atom (or an electron) from a reduced donor in a diffusion-controlled reaction. If the donor is a redox protein, the oxidation process can be used to initiate an electron transfer sequence involving either intramolecular or intermolecular reactions. If the donor is an organic compound such as EDTA, the neutral flavin semiquinone will be produced by H atom abstraction; this is a strong reductant and can subsequently transfer a hydrogen atom (or an electron) to an oxidized redox protein, thereby again initiating a sequence of intramolecular or intermolecular processes. If flavin photoexcitation is accomplished using a pulsed laser light source, the initiation of these protein electron transfer reactions can be made to occur in the nanosecond to microsecond time domain, and the sequence of events can be followed by time-resolved spectrophotometry to obtain rate constants and thus mechanistic information. The present paper describes this technology, and selected examples of its use in the investigation of redox protein mechanisms are given. 相似文献
28.
Alexander Tischer Pranathi Madde Laurie Moon-Tasson Matthew Auton 《Biophysical journal》2014,107(5):1185-1195
The primary hemostatic von Willebrand factor (vWF) functions to sequester platelets from rheological blood flow and mediates their adhesion to damaged subendothelium at sites of vascular injury. We have surveyed the effect of 16 disease-causing mutations identified in patients diagnosed with the bleeding diathesis disorder, von Willebrand disease (vWD), on the structure and rheology of vWF A1 domain adhesiveness to the platelet GPIbα receptor. These mutations have a dynamic phenotypical range of bleeding from lack of platelet adhesion to severe thrombocytopenia. Using new rheological tools in combination with classical thermodynamic, biophysical, and spectroscopic metrics, we establish a high propensity of the A1 domain to misfold to pathological molten globule conformations that differentially alter the strength of platelet adhesion under shear flow. Rheodynamic analysis establishes a quantitative rank order between shear-rate-dependent platelet-translocation pause times that linearly correlate with clinically reported measures of patient platelet counts and the severity of thrombocytopenia. These results suggest that specific secondary structure elements remaining in these pathological conformations of the A1 domain regulate GPIbα binding and the strength of vWF-platelet interactions, which affects the vWD functional phenotype and the severity of thrombocytopenia. 相似文献
29.
Hydrogen peroxide is more toxic to mammalian cells at 37 degrees C than 0 degree C at all concentrations studied. Histone-free nuclei (nucleoids) extracted from treated cells have a reduced ability to maintain positive DNA supercoiling, with the maximum effect at the higher temperature. Prior exposure of cells to sodium ascorbate at 0 degree C increased both toxicity and the inhibition of nuclear supercoil rewinding. After exposure at 0 degrees C, normal levels of supercoiling returned with both a fast and a slow component, kinetics characteristic of DNA single-strand break repair; the fast component was eliminated when cells were exposed at 37 degrees C due to in situ rejoining. At least a portion of the lethal lesions induced by hydrogen peroxide are DNA double-strand breaks (dsb) because the dsb repair-deficient mutant, xrs-5, is approximately two to three times more sensitive than wild-type cells over the initial portion of the survival curve. However, the increased toxicity found after exposure at 37 degrees C is observed equally in both cell lines, indicating that temperature-dependent cell killing is not directly linked to DNA dsb. It is suggested that cell killing at 37 degrees C is mediated through two linked processes. First, hydrogen peroxide may disrupt cation-stabilized nuclear supercoiling by direct ion oxidation. Second, as a part of the oxidation process, hydrogen peroxide will produce potentially cytotoxic free radicals close to the DNA-linked metal site, limited in extent only by the presence of chemicals capable of reducing metal ions prior to reoxidation. 相似文献
30.