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排序方式: 共有387条查询结果,搜索用时 15 毫秒
1.
2.
Solid-phase synthesis of 16 potent (selective and nonselective) in vivo antagonists of oxytocin 总被引:7,自引:0,他引:7
M Manning M Kruszynski K Bankowski A Olma B Lammek L L Cheng W A Klis J Seto J Haldar W H Sawyer 《Journal of medicinal chemistry》1989,32(2):382-391
We describe the synthesis and some pharmacological properties of 16 new in vivo antagonists of oxytocin. These are based on modifications of three peptides: A, B, and C. A is our previously reported potent and selective antagonist of the vasopressor (V1 receptor) responses to arginine-vasopressin (AVP)/weak oxytocin antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid), 2-O-methyltyrosine]arginine-vasopressin (d(CH2)5[Tyr(Me)2]AVP. B reported here, the Ile3 analogue of A, is d(CH2)5[Tyr(Me)2]AVT (5 below) and C is our previously reported potent nonselective oxytocin antagonist/AVP V1 antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O- methyltyrosine,8-ornithine]vasotocin (d(CH2)5[Tyr(Me)2]OVT). The following substitutions and deletions, alone or in combination, were employed in A, B, and C: 1-deaminopenicillamine (dP); D-Tyr(Alk)2 (where Alk = Me or Et), D-Phe2; Val4, Thr4; delta 3-Pro7; Lys8, Cit8; desGly9, desGly-NH2(9), Ala-NH2(9); Leu-NH2(9); Arg-NH2(9). The 16 new analogues are (1) d(CH2)5[D-Tyr(Me)2]AVP, (2) d(CH2)5[D-Tyr(Me)2, Val4,delta 3-Pro7]AVP, (3) d(CH2)5[D-Tyr-(Et)2, Val4,Lys8]VP, (4) d(CH2)5[D-Tyr(Et)2,Val4,Cit8]VP, (5) d(CH2)5[Tyr(Me)2]AVT, (6) d(CH2)5[Tyr(Me)2,Lys8]VT, (7) dP[Tyr(Me)2]AVT, (8) dP[Tyr(Me)2,Val4]AVT, (9) d(CH2)5[D-Tyr(Me)2, Val4]AVT, (10) d(CH2)5[D-Phe2,Val4]AVT, (11) d(CH2)5[Tyr(Me)2,Thr4]OVT, (12) d(CH2)5[Tyr(Me)2,Thr4,Ala-NH2(9)]OVT, (13) d(CH2)5[Tyr(Me)2,Thr4,Leu-NH2(9)]OVT, (14) d(CH2)5[Tyr(Me)2,Thr4,Arg-NH2(9)]OVT, (15) desGly-NH2(9),d(CH2)5[Tyr(Me)2,Thr4]OVT, (16) desGly9,d(CH2)5[Tyr(Me)2,Thr4]OVT. 1-4 are analogues of A, 5-10 are analogues of B, and 11-16 are analogues of C. Their protected precursors were synthesized either entirely by the solid-phase method or by a combination of solid-phase and solution methods (1 + 8 or 8 + 1 couplings). All analogues were tested in rats for agonistic and antagonistic activities in oxytocic (in vitro, without and with Mg2+, and in vivo) assays as well as by antidiuretic and vasopressor assays. All analogues exhibit potent oxytocic antagonism in vitro and in vivo. With an in vitro pA2 (in the absence of Mg2+) = 9.12 +/- 0.09, dP[Tyr(Me)2]AVT is (7) one of the most potent in vitro oxytocin antagonists reported to date. Fifteen of these analogues (all but 6) appear as potent or more potent in vivo oxytocin antagonists than C (pA2 = 7.37 +/- 0.17). Analogues 1-9 and 14 are potent AVP V1 antagonists. Their anti-V1 pA2 values range from 7.92 to 8.45. They are thus nonselective oxytocin antagonists.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
3.
CA von Arnim R Spoelgen ID Peltan M Deng S Courchesne M Koker T Matsui H Kowa SF Lichtenthaler MC Irizarry BT Hyman 《The Journal of neuroscience》2006,26(39):9913-9922
The beta-amyloid (Abeta) precursor protein (APP) is cleaved sequentially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized gamma-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from beta-cleavage but surprisingly reduced Abeta. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP beta-cleavage products from becoming substrates for gamma-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD. 相似文献
4.
应用放射配体结合法证实大鼠胸腺内存在降黑素特异结合部位,该结合位点可以满足特异结合部位的基本条件:1.低结合容量;2.高亲和力;3.可饱和性;4.可逆性;5.对降黑素高度特异性。此外,该特异结合位点具昼夜节律;亚细胞分布的研究表明以细胞核含量最高,线粒体次之,并具有年龄依赖性降低,以出生时最高。 相似文献
5.
Kung FT; Chen WJ; Chou HH; Ko SF; Chang SY 《Human reproduction (Oxford, England)》1997,12(8):1649-1653
We report a rare case of early-stage endometrial adenocarcinoma in a 22
year old nullipara with polycystic ovaries undergoing conservative
treatment. Pretreatment evaluation including tumour grade, depth of
myometrial invasion, tumour size, hormone receptor status and flow
cytometric analysis indicated a favourable prognosis. The patient underwent
repeat endometrial curettage and a 6 month period of therapy with megestrol
acetate and tamoxifen. A combination contraceptive pill was then prescribed
to ensure withdrawal of the menstrual cycle thereafter. Now, 1 year after
the last curettage, there is no evidence of disease. During the treatment
period, hysteroscopy allowed for a more precise approach in panoramically
examining the tumour nest in the endometrial cavity, and the subsequent
endometrial response to hormone therapy. Laparoscopy using bulldog clamps
applied to the isthmic portion of the Fallopian tubes prevented i.p. spread
of endometrial tissue from retrograde regurgitation during hysteroscopy.
Laparoscopic ovarian electrocautery resulted in the reduction of abnormal
hypervascularization on the surface of polycystic ovaries postoperatively
but caused a peri-ovarian adhesion complication. It is interesting that
this case posed a unique opportunity to demonstrate the tumour regression
under the assistance of laparoscopy and hysteroscopy.
相似文献
6.
Pierre Robin sequence (PRS) describes a small mandible with retrognathia, an elevated and posteriorly positioned tongue, and an associated U-shaped cleft palate. The retracted tongue may obstruct the airway leading to respiratory failure, with failure to thrive and adverse neurodevelopmental outcomes if not addressed. If the airway obstruction cannot be overcome with conservative measures, there are non-surgical and surgical options. A nasopharyngeal prong (NPP) is a non-surgical, temporary treatment that avoids the complications inherent in an operation, especially given the natural history of mandibular growth and improved airway obstruction in PRS. Although the use of a prong requires training, support, and follow up, it effectively bypasses the obstruction in the majority of children with PRS, and allows the child to outgrow the airway obstruction until the prong is no longer required. On average, the prong can be removed between 6 and 12 months of age. 相似文献
7.
A. A. van Bodegraven C. J. M. Böhmer R. A. Manoliu E. Paalman A. H. van der Klis A. J. M. Roex A. M. Kruishoop W. L. J. M. Devillé J. Lourens 《Scandinavian journal of gastroenterology》2013,48(9):993-998
Background: A high risk of developing sludge or gallstones has been associated with pregnancy. The aim of this study was to relate the prevalence of sludge and gallstones during and shortly after pregnancy to fasting gallbladder volume as an indicator of gallbladder motility. Methods: The population included 114 apparently healthy pregnant women from the Outpatient Clinic of Obstetrics of a large regional hospital and from the practices of regional midwives. Ultrasonography of the gallbladder was performed at weeks 15, 25, and 35 of gestation and at week 3 and month 6 postpartum. Results: At gestational week 15, 3 women had gallstones and 10 had sludge (mean volume, 33.8 ml), and 99 women had a normal gallbladder (mean volume, 30.5 ml). At week 25, 1 woman with a normal gallbladder formed gallstones and underwent cholecystectomy shortly after, and 22 women had sludge, of whom 13 had a normal gallbladder at first examination (mean volume, 33.2 ml). In 88 women with normal gallbladders (of whom 2 had sludge at week 15) mean volume was 31.9 ml. At week 35, 2 women had gallstones, and 21 had sludge (mean volume, 30.5 ml). In the remaining 79 women the gallbladders were clear (mean volume, 29.5 ml). Eight women developed sludge and two women gallstones in normal gallbladders at week 25. Seven women with sludge at week 25 had a normal gallbladder at week 35. Three weeks postpartum only 10 of 100 women had sludge (mean volume, 29.1 ml). Of these 10, 9 women had a normal gallbladder at week 35. Twenty of 21 women with sludge at week 35 had normal gallbladders week 3 postpartum. Gallstones found at week 35 had disappeared. In the women with a normal gallbladder the mean volume was decreased to 19.7 ml (P &;lt; 0.0001). Six months postpartum, sludge was found in 6 (mean volume, 18.4 ml) of 93 women (mean volume, 20.3 ml), of whom 5 had a normal gallbladder at week 3 postpartum. Only 61 women showed a normal gallbladder at each examination of the study. No differences in patient characteristics were found between women with normal gallbladders and those with sludge or gallstones. Conclusions: Fasting gallbladder volume was increased in all pregnant women. This could not explain the formation of sludge or gallstones during gestation. Decrement of gallbladder volumes after delivery was faster in normal, clear gallbladders. More than a prerequisite, increased fasting gallbladder volume seemed to be a permissive factor of pregnancy-associated gallstone formation. 相似文献
8.
9.
Kameoka J; Sato T; Torimoto Y; Sugita K; Soiffer RJ; Schlossman SF; Ritz J; Morimoto C 《Blood》1995,85(4):1132-1137
Patients who have undergone allogeneic bone marrow transplantation (allo-BMT) are susceptible to a variety of opportunistic infectious complications in the months to years after engraftment. Impaired in vitro T-cell functions have been documented in these patients, and these T-cell dysfunctions contribute to the prolonged immune deficiency after allo-BMT. In the present study, we examined the expression of CD26 as well as the reconstitution of CD26-mediated T-cell costimulation via the CD3 and CD2 pathways at various times in patients aged greater than 18 years after CD6-positive, T-cell depleted allo- BMT. We found that the percentage of CD26- and CD3-positive cells, as well as the levels of expression of both antigens, was lower than in normal controls during the first 4 months after CD6-depleted allo-BMT. Subsequently, the amount of lymphocytes expressing CD3 and CD26 and the quantitative surface expression of CD3 and CD26 were not significantly different in patients and normal controls. Functional studies showed that CD26-mediated T-cell proliferation via the CD3 pathway was considerably improved and almost reached normal levels by 1 year, whereas recovery of CD26-mediated T-cell proliferation via the CD2 pathway was delayed for at least 2 years after CD6-depleted allo-BMT. As CD26 involvement in the regulation of human thymocyte activation is restricted preferentially to the CD3 pathway--unlike its involvement with both CD3 and CD2 pathways of peripheral T cells--our results suggest that the different effects of CD26-mediated costimulation via the CD3 and CD2 pathways after CD6-depleted allo-BMT may be a reflection of peripheral T-cell immaturity in those individuals, similar to that seen in mature medullary thymocytes or cord T lymphocytes. 相似文献
10.
Fc gamma receptor II (CD32) on malignant B cells influences modulation induced by anti-CD19 monoclonal antibody 总被引:1,自引:1,他引:1
Vervoordeldonk SF; Merle PA; van Leeuwen EF; van der Schoot CE; von dem Borne AE; Slaper-Cortenbach IC 《Blood》1994,83(6):1632-1639
Antigenic modulation is one of many factors determining the effectiveness of monoclonal antibody (MoAb)-mediated therapy. To select the isotype of a CD19 MoAb most suitable for radioimmunotherapy of patients with B-cell malignancies, we studied the influence of MoAb isotype on modulation, after binding of the MoAb to different cell-line cells. The CD19-IgG1 MoAb was found to induce modulation of CD19 antigens on Daudi cell line cells more rapidly than did its IgG2a switch variant. We provide evidence that this difference in modulation rate is caused by the expression of Fc gamma receptor II (Fc gamma RII) on these cells. Experiments aimed at elucidating the mechanism of Fc gamma RII involvement in modulation induction by CD19-IgG1 showed that Fc gamma RII did not comodulate with CD19 MoAbs. However, cocrosslinking of CD19 and Fc gamma RII with CD19-IgG1 MoAb resulted in enhanced calcium mobilization in Daudi cells. This increased signal induction accompanies the enhanced capping and subsequent modulation of CD19 antigens. Because Fc gamma RII is expressed in varying densities on malignant B cells in all differentiation stages, our results have implications for the MoAb isotype most suitable for use in MoAb-based therapy of patients with B-cell malignancies. 相似文献