A Novel, High-Affinity, Fluorescent Progesterone Receptor Antagonist. Synthesis and in Vitro Studies

2004 ◽  
Vol 15 (2) ◽  
pp. 359-365 ◽  
Author(s):  
Claudia Hödl ◽  
Wolfgang S. L. Strauss ◽  
Reinhard Sailer ◽  
Christoph Seger ◽  
Rudolf Steiner ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Receptor Antagonist ◽  
In Vitro Studies ◽  
High Affinity

Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: Possible confounding effects on in vivo and in vitro studies

2012 ◽  
Vol 22 (21) ◽  
pp. 6661-6664 ◽  
Author(s):  
Charles J. McElhinny ◽  
Anita H. Lewin ◽  
S. Wayne Mascarella ◽  
Scott Runyon ◽  
Lawrence Brieaddy ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
In Vitro Studies

scholarly journals in vivo and in vitro studies on a new type of plasminogen activator with fibrin high-affinity from human urine.

1993 ◽  
Vol 61 ◽  
pp. 78
Author(s):  
Shigeru Taguchi ◽  
Kimihiro Ogino ◽  
Chiaki Shirato ◽  
Isao Aoju ◽  
Kyozo Ishikawa ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Human Urine ◽  
In Vitro Studies ◽  
High Affinity ◽  
New Type

Growth of the endometrium and cotyledons during pregnancy in the ewe: rates of protein secretion and synthesis and nuclear and cytosol steroid hormone receptor levels

1983 ◽  
Vol 96 (1) ◽  
pp. 137-146 ◽  
Author(s):  
B. G. Miller ◽  
R. Tassell ◽  
G. M. Stone
Keyword(s):  
Progesterone Receptor ◽  
Protein Secretion ◽  
Time Course ◽  
Steroid Hormone ◽  
Secretory Activity ◽  
The Other ◽  
Steroid Hormone Receptor ◽  
High Affinity ◽  
Nuclear Progesterone Receptor

The time-course of cell hypertrophy and changes in in-vitro rates of secretion and synthesis of protein in intercaruncular and caruncular endometrium and maternal and fetal cotyledonary placenta have been examined during days 0–112 of pregnancy in the ewe. The concentrations of high-affinity receptors for oestradiol and progesterone in nuclear and cytosol fractions from these tissues were also determined. Protein secretion by intercaruncular endometrium increased 25-fold between days 0 and 84. On day 84 10−5 m-colchicine blocked 75% of total secretion. Protein secretion did not increase in the other tissues. Protein synthesis and RNA: DNA ratio in intercaruncular endometrium increased steadily between days 0 and 112, whereas they did not change in caruncular endometrium between days 0 and 28 and declined in cotyledon between days 56 and 112. The levels of cytosol receptor for oestradiol and progesterone and of nuclear receptor for oestradiol in all tissues during days 56–112 were very low in relation to the corresponding levels in caruncular endometrium on day 0. The level of nuclear progesterone receptor in caruncular endometrium increased threefold between oestrus and day 28. The level of this receptor in cotyledon remained low on days 56–112, but in intercaruncular endometrium it increased to high values on days 84–112. The results demonstrated a major surge in secretory activity by the intercaruncular endometrium at around mid-gestation, which was associated with a marked increase in nuclear progesterone receptor levels but only a low level of nuclear oestradiol receptor. The observations do not suggest any important role for oestradiol or progesterone in the growth of fetal and maternal cotyledon.

In Vitro Antisickling Effects of Novel Pyridyl Derivatives with Enhanced Potency.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2347-2347
Author(s):  
Osheiza Y. Abdulmalik ◽  
Martin K. Safo ◽  
Gajanan Joshi ◽  
Jisheng Yang ◽  
Qiukan Chen ◽  
...  
Keyword(s):  
Schiff Base ◽  
Plasma Concentration ◽  
In Vitro Studies ◽  
Dependent Manner ◽  
High Affinity ◽  
Concentration Time ◽  
Hb S ◽  
Dose Dependent ◽  
Derivatives Of

Abstract Chemical modification of sickle hemoglobin (Hb S) to form stable high affinity Schiff-base adducts has been an attractive approach towards finding a potential therapeutic option for sickle cell disease (SCD). An ideal candidate drug should rapidly enter the bloodstream, permeate red blood cell membrane, bind specifically with intracellular Hb S and inhibit cell sickling with minimal adverse effect. In an effort to find drugs that satisfy these criteria, we recently designed, synthesized and studied three novel benzaldehydes (INN-296, INN-298 and INN-312) with enhanced potency. The compounds are pyridyl derivatives of benzaldehyde, and hence, combine structural features of two previously determined antisickling agents: vanillin and pyridoxal. All three compounds shifted the allosteric equilibrium of Hb S toward the oxy- or R-state by destabilizing the deoxy- or T-state. The results of in vitro studies of the antisickling effects of a representative compound (INN-312) are reported. Upon incubation of suspensions of sickle erythrocytes (SS cells) with 0.5, 1 or 2 mM of INN-312 under hypoxia (4% O2 :96% N2) at 37°C, sickling of SS cells was inhibited in a dose-dependent manner (15 ± 2, 44 ± 10 and 81 ± 8% inhibition, respectively). Cation-exchange HPLC analysis of lysates from the pre-incubated SS cells revealed a new peak in addition to the original Hb S peak, indicative of formation of Schiff-base adducts of Hb. Oxygen equilibrium curves (OECs) of SS-cell suspensions and lysates were shifted toward the left in a dose-dependent manner. X-ray crystal structures of these derivatives revealed their symmetric binding to the two N-terminal αVal1 of Hb S, and seem to indicate that their superior antisickling activity may arise from effector-induced interference with Hb S polymerization, as well as shifting the OEC to the high affinity state. In vitro studies on INN-296 and INN-298 showed similar results. Studies in vivo were performed using transgenic sickle mice (3 mice per group). The mice were treated intraperitoneally with single doses of 50, 100 or 150 mg/kg of INN-312. To study pharmacokinetic profiles of INN-312 in treated mice, blood samples (~20 μl each) were collected under anesthesia via retro-orbital venipuncture into EDTA tubes at 30 min, 1 h and every hour afterwards for 5 hours. Plasma from each sample was de-proteinized and analyzed by reversed-phase HPLC for quantification of INN-312 present in the blood. A non-compartmental pharmacokinetic model with first-order elimination rate was used to determine the plasma concentration-time data using PK Solutions 2.0 software (SUMMIT Research Services, Montrose, CO, USA). The area under the plasma concentration curve (AUC) increased in a dose-dependent manner (314 ± 22 μg/ml/min, 648 ± 33 μg/ml/min and 1044 ± 63 μg/ml/min in mice treated with 50, 100 and 150 mg/kg, respectively). The terminal half-life (T1/2= 0.75 ± 0.15 h), peak concentration time (Tmax= 0.5 h), and mean resident time (MRT= 1.2 ± 0.2 h) values were consistent for all three dosage groups. The observed maximum plasma concentration (Cmax)was also increased in a dose-dependent manner. These novel pyridyl derivatives of benzaldehyde shifted the position of Hb OEC toward the left most strongly among various compounds reported to date. Further detailed studies are necessary to validate this approach to developing better antisickling agents.

scholarly journals In vitro pharmacological profile of YM-43611, a novel D2-like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors

1996 ◽  
Vol 117 (8) ◽  
pp. 1625-1632 ◽  
Author(s):  
Kazuyuki Hidaka ◽  
Shoko Tada ◽  
Mitsuyuki Matsumoto ◽  
Junya Ohmori ◽  
Yoshikazu Tasaki ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Pharmacological Profile ◽  
High Affinity ◽  
Dopamine D3

58 STAGE–SPECIFIC EFFECTS OF THE PROGESTERONE RECEPTOR ANTAGONIST, RU486, ON EARLY BOVINE EMBRYO DEVELOPMENT

2012 ◽  
Vol 24 (1) ◽  
pp. 141
Author(s):  
C. M. O'Meara ◽  
T. Fair ◽  
P. Lonergan
Keyword(s):  
Progesterone Receptor ◽  
Receptor Antagonist ◽  
Embryo Development ◽  
Blastocyst Stage ◽  
Significant Decline ◽  
Bovine Embryo ◽  
Blastocyst Development ◽  
Cleavage Rate ◽  
Antagonist Ru486

Progesterone plays a key role in the reproductive events associated with pregnancy establishment and maintenance. High concentrations of circulating progesterone in the immediate post-conception period are associated with an advancement of conceptus elongation, an associated increase in interferon-tau production and higher pregnancy rates in cattle. Progesterone-induced changes in the uterine environment are thought to be responsible for the reported advancement in conceptus elongation; however, the function of the progesterone receptor in embryos is not known. Therefore, the aim of the current study was to examine the effect of adding a progesterone receptor antagonist (mifepristone, RU486) at various stages of early embryonic development and at varying concentrations to examine the effects on subsequent embryo development in vitro. Bovine zygotes (n = 2902), 2-cell (n = 1991) and 8-cell (n = 1244) embryos, derived by in vitro maturation and fertilization, were cultured in synthetic oviduct fluid medium in the absence or presence of RU486 at concentrations ranging from 0.0004 to 20 μg mL–1. Cleavage rate (of zygotes), 8-cell development rate (of 2-cell embryos) and development to the blastocyst stage (for all cell stages) were recorded at Day 2, 3 and 8 post-insemination (day of IVF = Day 0), respectively. Cultures of zygotes in the presence of RU486 at concentrations of 0.004 and 0.04 μg mL–1 resulted in a decline in cleavage rate (62.5 ± 2.55% and 48.8 ± 5.07% for respective treatments vs controls without RU486 81.9 ± 5.97%; P ≤ 0.05). These same concentrations resulted in a significant decline in blastocyst development on Day 8 (18.8 ± 1.82% and 17.4 ± 4.85% for respective treatments compared to controls 35.1 ± 4.89%; P ≤ 0.05). Cultures at concentrations of 0.4 μg mL–1 resulted in a 10-fold decrease in blastocyst development (3.3 ± 1.3%; P ≤ 0.05) and concentrations in excess of 10 μg mL–1 completely ablated blastocyst development (P ≤ 0.05). Cultures of 2-cell embryos with RU486 at concentrations below 8 μg mL–1 had no effect on 8-cell rate or blastocyst development. However, cultures with RU486 at 10 μg mL–1 resulted in a significant decline in the proportion reaching the 8-cell stage (59.1 ± 4.59% vs 38.1 ± 2.13% for control and treated, respectively) and developing to the blastocyst stage (32.8 ± 4.68% vs 17.8 ± 3.77% for control and treated, respectively; P ≤ 0.05). Cultures with RU486 at a concentration of 20 μg mL–1 resulted in a dramatic effect in 8-cell rate (16.3 ± 2.55%; P ≤ 0.05) and prevented blastocyst development. Similarly, cultures of 8-cell embryos with RU486 at concentrations at or below 10 μg mL–1 had no effect on blastocyst development. However, cultures at concentrations of 15 or 20 μg mL–1 resulted in no blastocyst development. In conclusion, addition of the progesterone and glucocorticoid receptor antagonist RU486 to culture media has a clear stage-specific and concentration-dependent effect on bovine embryo development, which is more pronounced at earlier developmental stages. Supported by Science Foundation Ireland (07/SRC/B1156).

Radiosynthesis of high affinity fluorine-18 labeled GnRH peptide analogues: in vitro studies and in vivo assessment of brain uptake in rats

MedChemComm ◽  
2015 ◽  
Vol 6 (4) ◽  
pp. 708-714 ◽  
Author(s):  
Dag Erlend Olberg ◽  
Sven H. Hausner ◽  
Nadine Bauer ◽  
Jo Klaveness ◽  
Bård Indrevoll ◽  
...  
Keyword(s):  
Gnrh Receptor ◽  
Receptor Expression ◽  
In Vitro Studies ◽  
Imaging Agents ◽  
Brain Uptake ◽  
High Affinity ◽  
Peptide Analogues ◽  
In Vivo Assessment

A series of high affinity 18F-GnRH peptides have been synthesized and show utility as imaging agents for GnRH receptor expression in vivo.

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