Synthesis of Multivalent [Lys8]-Oxytocin Dendrimers that Inhibit Visceral Nociceptive Responses

2017 ◽  
Vol 70 (2) ◽  
pp. 162 ◽  
Author(s):  
Jingjing Wan ◽  
Mehdi Mobli ◽  
Andreas Brust ◽  
Markus Muttenthaler ◽  
Åsa Andersson ◽  
...  
Keyword(s):  
Binding Affinity ◽  
2D Nmr ◽  
Oxytocin Receptor ◽  
Chronic Abdominal Pain ◽  
Peptide Dendrimers ◽  
Oxytocin Receptors ◽  
Nociceptive Responses ◽  
Affinity Receptor ◽  
Selectivity Change

Peptide dendrimers are a novel class of precisely defined macromolecules of emerging interest. Here, we describe the synthesis, structure, binding affinity, receptor selectivity, functional activity, and antinociceptive properties of oxytocin-related dendrimers containing up to 16 copies of [Lys8]-oxytocin or LVT. These were generated using a copper(i)-catalyzed azide–alkyne cycloaddition (CuAAc) reaction with azido-pegylated LVT peptides on an alkyne–polylysine scaffold. 2D NMR analysis demonstrated that each attached LVT ligand was freely rotating and maintained identical 3D structures in each dendrimeric macromolecule. The binding affinity Ki at the oxytocin receptor increased approximately 17-, 12-, 3-, and 1.5-fold respectively for the 2-, 4-, 8-, and 16-mer dendrimeric LVT conjugates, compared with monomer azido-pegylated LVT (Ki = 9.5 nM), consistent with a multivalency effect. A similar trend in affinity was also observed at the related human V1a, V1b, and V2 receptors, with no significant selectivity change observed across this family of receptors. All LVT dendrimers were functionally active in vitro on human oxytocin receptors and inhibited colonic nociceptors potently in a mouse model of chronic abdominal pain.

Changes in progesterone and oestrogen receptor mRNA and protein and oxytocin receptors in endometrium of ewes after intrauterine injection of ovine trophoblast interferon

1993 ◽  
Vol 10 (2) ◽  
pp. 185-192 ◽  
Author(s):  
M A Mirando ◽  
J P Harney ◽  
Y Zhou ◽  
T F Ogle ◽  
T L Ott ◽  
...  
Keyword(s):  
Oestrogen Receptor ◽  
Inositol Phosphate ◽  
Oxytocin Receptor ◽  
Secretory Proteins ◽  
Type I ◽  
Oestrogen Receptors ◽  
Receptor Mrna ◽  
Oxytocin Receptors ◽  
Highly Correlated

ABSTRACT This study determined whether twice-daily intrauterine injections of ovine conceptus secretory proteins (oCSP) containing type-I trophoblast interferon (25 μg/uterine horn) from day 11 to day 15 post-oestrus (oestrus = day 0) could alter the binding capacities of endometrial receptors for oxytocin, progesterone and oestrogen in cyclic ewes when compared with control ewes receiving serum protein (SP) injections. Injections of oCSP on days 11–15 post-oestrus decreased concentrations of oestrogen receptors (P<0·06), oestrogen receptor mRNA (P<0·05) and progesterone receptors (P<0·08) in endometrium on day 16 when compared with SP-infused control ewes, which were undergoing corpus luteum regression on days 14–16. Injection of oCSP also decreased the number (P<0·10) and affinity (P<0·06) of oxytocin receptors. Inositol phosphate formation induced in the endometrium on day 16 by 100 nm oxytocin in vitro was highly correlated with the concentration (r≥0·93, P<0·001) and Kd (r= –0·91, P<0·01) of oxytocin receptors in SP-infused ewes, but was not as highly correlated with concentration (r≤0·83, P<0·06) and Kd (r≤ –0·40, P>0·40) of oxytocin receptors in oCSP-infused ewes. This indicates that oCSP disrupted the relationship between oxytocin receptor binding and oxytocin-induced activation of its second messenger system. These results indicate that antiluteolytic type-I trophoblast interferon may prevent oxytocininduced luteolytic pulsatile secretion of prostaglandin F2α during maternal recognition of pregnancy in sheep, by reducing the synthesis and affinity of endometrial oxytocin receptors. Inhibition of other components of the oxytocin receptor—phospholipase C system by ovine trophoblast interferon may also be involved in reducing endometrial responsiveness to oxytocin. Ovine trophoblast interferon may inhibit the synthesis of endometrial oestrogen receptors to inhibit responsiveness to oxytocin during early pregnancy in ewes.

Characterization and autoradiographical localization of oxytocin receptors within the ovine endometrium in relation to post-partum corpus luteum function

1991 ◽  
Vol 128 (2) ◽  
pp. 253-NP ◽  
Author(s):  
J. M. Wallace ◽  
P. J. Morgan ◽  
R. Helliwell ◽  
R. P. Aitken ◽  
M. Cheyne ◽  
...  
Keyword(s):  
Post Partum ◽  
Oxytocin Receptor ◽  
Corpora Lutea ◽  
Uterine Endometrium ◽  
Oxytocin Receptors ◽  
High Incidence ◽  
Prostaglandin F ◽  
Group A ◽  
And Control

ABSTRACT The induction of ovulation in early post-partum ewes is associated with a high incidence of premature luteal regression which is independent of the suckling stimulus but dependent on the stage post partum. The aim of the present study was to determine whether oxytocin receptors are present on uterine endometrium early in the luteal phase and hence ascertain whether oxytocin-induced uterine prostaglandin F2α release is a possible mechanism involved in the premature regression of these post-partum corpora lutea. Ovarian and uterine tissues were collected on day 4 of the cycle in ewes induced to ovulate at either 21 or 35 days post partum (n = 4 per group). A further four cyclic ewes were similarly synchronized to ovulate and acted as controls. Corpora lutea from the 21-day post-partum group were significantly (P < 0·01) smaller, had a lower progesterone content and a reduced capacity to secrete progesterone in vitro than corpora lutea from 35-day post-partum or control ewes. A highly specific oxytocin receptor ligand 125I-labelled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH29]-vasotocin was used to localize and characterize high affinity oxytocin receptors in uterine endometrium (dissociation constant 145 pmol/l). Oxytocin receptor concentrations in endometrium from ewes induced to ovulate at 21 days post partum were on average five-fold higher (P < 0·05) than in 35-day post-partum and control groups. Journal of Endocrinology (1991) 128, 253–260

Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors

2020 ◽  
Vol 20 (18) ◽  
pp. 1628-1639
Author(s):  
Sergi Gómez-Ganau ◽  
Josefa Castillo ◽  
Andrés Cervantes ◽  
Jesus Vicente de Julián-Ortiz ◽  
Rafael Gozalbes
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Binding Affinity ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Significant Activity ◽  
Epidermal Growth

Background: The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma. Methods: We have followed a structure-based virtual screening (SBVS) procedure with a library composed of several commercial collections of chemicals (615,462 compounds in total) and the 3D structure of EGFR obtained from the Protein Data Bank (PDB code: 1M17). The docking results from this campaign were then ranked according to the theoretical binding affinity of these molecules to EGFR, and compared with the binding affinity of erlotinib, a well-known EGFR inhibitor. A total of 23 top-rated commercial compounds displaying potential binding affinities similar or even better than erlotinib were selected for experimental evaluation. In vitro assays in different cell lines were performed. A preliminary test was carried out with a simple and standard quick cell proliferation assay kit, and six compounds showed significant activity when compared to positive control. Then, viability and cell proliferation of these compounds were further tested using a protocol based on propidium iodide (PI) and flow cytometry in HCT116, Caco-2 and H358 cell lines. Results: The whole six compounds displayed good effects when compared with erlotinib at 30 μM. When reducing the concentration to 10μM, the activity of the 6 compounds depends on the cell line used: the six compounds showed inhibitory activity with HCT116, two compounds showed inhibition with Caco-2, and three compounds showed inhibitory effects with H358. At 2 μM, one compound showed inhibiting effects close to those from erlotinib. Conclusion: Therefore, these compounds could be considered as potential primary hits, acting as promising starting points to expand the therapeutic options against a wide range of cancers.

Synthesis, Antimicrobial Evaluation and Docking Study of Novel Thiosemicarbazone clubbed with 1,2,3-Triazoles

2020 ◽  
Vol 16 ◽  
Author(s):  
Adinath D. Badar ◽  
Shubham M. Sulakhe ◽  
Mahesh B. Muluk ◽  
Naziya N. M. A. Rehman ◽  
Prashant P. Dixit ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Biological Activities ◽  
Dna Gyrase ◽  
Docking Study ◽  
Antimicrobial Activities ◽  
Diffusion Method ◽  
Molecular Docking Study ◽  
Triazole Derivatives ◽  
Antibacterial And Antifungal

Background: Thiosemicarbazone, 1,2,3-triazole and their derivatives received great pharmaceutical importance due to their prominent biological activities. In the present study, the molecular hybrid thiosemicarbazone-1,2,3-triazoles derivatives were synthesized and screened for their antimicrobial activities. Methods: A series of thiosemicarbazone clubbed with 1,2,3-triazole derivatives were synthesized via click chemistry approach in good yields. The structures of synthesized compounds were assigned by their spectral data. The in vitro antimicrobial activity was performed by the agar well diffusion method. A molecular docking study was performed to identify the possible mode of action of synthesized derivatives. Results: The compounds 5d, 5h, 5i and 5k have exhibited excellent antimicrobial activities against both antibacterial and antifungal pathogens. The active thiosemicarbazone-1,2,3-triazole derivatives have shown excellent binding affinity towards DNA gyrase. Conclusion: The molecular hybrid thiosemicarbazone-1,2,3-triazole derivatives were synthesized. The newly synthesized compounds were evaluated for their antimicrobial activities. Few of the thiosemicarbazone-1,2,3-triazoles derivatives have exhibited good antimicrobial activities. They have been shown excellent binding affinity towards DNA gyrase.

scholarly journals Nociceptive Sensitization by Activation of Protease-Activated Receptor 2 in a Rat Model of Incisional Pain

2021 ◽  
Vol 11 (2) ◽  
pp. 144
Author(s):  
Kanta Kido ◽  
Norika Katagiri ◽  
Hiromasa Kawana ◽  
Shigekazu Sugino ◽  
Masanori Yamauchi ◽  
...  
Keyword(s):  
Postoperative Pain ◽  
Inflammatory Responses ◽  
Early Period ◽  
Intraplantar Injection ◽  
C Fibers ◽  
Nociceptive Responses ◽  
Incisional Pain ◽  
Protease Activated Receptor 2

Postoperative pain and consequent inflammatory responses after tissue incision adversely affects many surgical patients due to complicated mechanisms. In this study, we examined whether activation of protease-activated receptor 2 (PAR-2), which is stimulated by tryptase from mast cells, elicits nociception and whether the PAR-2 antagonist could reduce incisional nociceptive responses in vivo and in vitro. The effects of a selective PAR-2 antagonist, N3-methylbutyryl-N-6-aminohexanoyl-piperazine (ENMD-1068), pretreatment on pain behaviors were assessed after plantar incision in rats. The effects of a PAR-2 agonist, SLIGRL-NH2, on nociception was assessed after the injection into the hind paw. Furthermore, the responses of C-mechanosensitive nociceptors to the PAR-2 agonist were observed using an in vitro skin–nerve preparation as well. Intraplantar injection of SLIGRL-NH2 elicited spontaneous nociceptive behavior and hyperalgesia. Local administration of ENMD-1068 suppressed guarding behaviors, mechanical and heat hyperalgesia only within the first few hours after incision. SLIGRL-NH2 caused ongoing activity in 47% of C-mechanonociceptors in vitro. This study suggests that PAR-2 may support early nociception after incision by direct or indirect sensitization of C-fibers in rats. Moreover, PAR-2 may play a regulatory role in the early period of postoperative pain together with other co-factors to that contribute to postoperative pain.

Halo-phenolic metabolites and their in vitro antioxidant and cytotoxic activities from the Red Sea alga Avrainvillea amadelpha

2021 ◽  
Vol 76 (5-6) ◽  
pp. 213-218
Author(s):  
Usama W. Hawas ◽  
Lamia T. Abou El-Kassem ◽  
Radwan Al-farawati ◽  
Fekri M. Shaher
Keyword(s):  
2D Nmr ◽  
Cytotoxic Activities ◽  
Dpph Radical ◽  
Srb Assay ◽  
Phenolic Metabolites ◽  
2D Nmr Spectra ◽  
New Compounds ◽  
Benzaldehyde Derivatives ◽  
Mcf 7

Abstract From the green alga Avrainvillea amadelpha, two new naturally halo-benzaldehyde derivatives were isolated by various chromatographic methods along with 10 known metabolites of bromophenols, sulfonoglycolipid, and steroids. Based on the 1D and 2D NMR spectra as well as on MS data, the structures of the new compounds were identified as 5-bromo-2-(3-bromo-4-hydroxybenzyl)-3,4-dihydroxybenzaldehyde named avrainvilleal (1), and 3-iodo-4-hydroxy-benzaldehyde (2). Using SRB assay, both compounds showed mild and weak cytotoxic activity against HeLa and MCF-7 cancer cell lines, compared to the good activity of their extract (IC50 values 3.1 and 4.3 μg/mL, respectively). However, avrainvilleal (1) displayed an effective scavenged DPPH radical activity with IC50 value 3.5 μM, compared to the antioxidant quercetin with IC50 value 1.5 μM.

scholarly journals Unusual derivatives from Hypericum scabrum

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sara Soroury ◽  
Mostafa Alilou ◽  
Thomas Gelbrich ◽  
Marzieh Tabefam ◽  
Ombeline Danton ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
2D Nmr ◽  
Moderate Activity ◽  
Trypanosoma Brucei Rhodesiense ◽  
L6 Cells ◽  
Aerial Parts ◽  
Hypericum Scabrum ◽  
New Compounds ◽  
Absolute Structure

AbstractThree new compounds (1–3) with unusual skeletons were isolated from the n-hexane extract of the air-dried aerial parts of Hypericum scabrum. Compound 1 represents the first example of an esterified polycyclic polyprenylated acylphloroglucinol that features a unique tricyclo-[4.3.1.11,4]-undecane skeleton. Compound 2 is a fairly simple MPAP, but with an unexpected cycloheptane ring decorated with prenyl substituents, and compound 3 has an unusual 5,5-spiroketal lactone core. Their structures were determined by extensive spectroscopic and spectrometric techniques (1D and 2D NMR, HRESI-TOFMS). Absolute configurations were established by ECD calculations, and the absolute structure of 2 was confirmed by a single crystal determination. Plausible biogenetic pathways of compounds 1–3 were also proposed. The in vitro antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense and Plasmodium falciparum and cytotoxicity against rat myoblast (L6) cells were determined. Compound 1 showed a moderate activity against T. brucei and P. falciparum, with IC50 values of 3.07 and 2.25 μM, respectively.

scholarly journals Beneficial effects of methanolic extract of Indigofera linnaei Ali. on the inflammatory and nociceptive responses in rodent models

2016 ◽  
Vol 52 (1) ◽  
pp. 113-123
Author(s):  
Raju Senthil Kumar ◽  
Balasubramanian Rajkapoor ◽  
Perumal Perumal ◽  
Sekar Vinoth Kumar ◽  
Arunachalam Suba Geetha
Keyword(s):  
Methanol Extract ◽  
Latency Period ◽  
Dependent Manner ◽  
Rodent Models ◽  
Hot Plate ◽  
Concentration Dependent Manner ◽  
Standard Drug ◽  
Beneficial Effects ◽  
Nociceptive Responses

ABSTRACT Indigofera linnaei Ali. (Tamil Name: Cheppu Nerinjil) belongs to the family Fabaceae, used for the treatment of various ailments in the traditional system of medicine. In the present study, the beneficial effects of methanol extract of whole plant of I. linnaei (MEIL) were evaluated on inflammation and nociception responses in rodent models. In vitro nitric oxide (NO), lipoxygenase (LOX) and cyclooxygense (COX) inhibitory activities were also performed to understand the mode of action. MEIL at the dose of 200 & 400 mg/kg, p.o. significantly inhibited carrageenan induced rat paw volume and reduced the weight of granuloma in cotton pellet granuloma model. The results obtained were comparable with the standard drug aceclofenac. The anti-nociceptive effect of MEIL in mice was evaluated in hot plate and acetic acid induced writhing model. The plant extract significantly reduced the number of writhes and the analgesic effect was higher than that of the standard drug aspirin. However, the extract fails to increase the latency period in hot plate method suggesting that the extract produce nociception by peripheral activity. The extract produced inhibitory effect on NO, LOX and COX in concentration dependent manner. The extract exhibited pronounced and selective COX-2 inhibition. Altogether, these results suggested that the methanol extract of Indigofera linnaei could be considered as a potential anti-inflammatory and analgesic agent.

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