taprenepag  (MedChemExpress)

Journal: Acta Pharmaceutica Sinica. B

Article Title: Modulating inflammatory prostaglandin E2 signaling to mitigate neurobehavioral comorbidities associated with seizure disorders

doi: 10.1016/j.apsb.2025.03.024

Figure Lengend Snippet: EP2 modulators that have been evaluated in human clinical trials. (A) Chemical structures of EP2-selective small-molecule antagonists PF-04418948 and benzoxazepine-52. (B) Chemical structures of selective EP2 agonists evatanepag (CP-533,536), taprenepag isopropyl (PF-0417329), and omidenepag isopropyl (Omlonti). (C) Cryo-EM density of EP2-G s in complex with EP2-selective agonist evatanepag (PDB: 7CX4 ) to highlight the ligand–receptor interaction. Reproduced with permission .

Article Snippet: Taprenepag isopropyl (also known as PF-0417329, B), another EP2-selective agonist developed by Pfizer, was studied in patients of primary open angle glaucoma and ocular hypertension ( https://clinicaltrials.gov/study/NCT00572455 ).

Techniques: Clinical Proteomics, Cryo-EM Sample Prep

Journal: Journal of neuroinflammation

Article Title: Taprenepag restores maternal-fetal interface homeostasis for the treatment of neurodevelopmental disorders.

doi: 10.1186/s12974-024-03300-7

Figure Lengend Snippet: Fig. 1 VPA exposure during pregnancy disrupted the MFB while RU486 treatment alleviated VPA induced damage. (A) Experimental flow chart. (B) Pla cental and fetal gadolinium leakage monitored by MRI. The black circle in the picture represents the fetus and placenta. (C) The mean pixel value of each fetus in the postcontrast images of A. (Hounsfield units, HU), (n = 4, pregnant mice, respectively). (D) and (E) The Gd leakage into fetuses (C) and placentas (D) from maternal blood was quantified by ICP-MS. (n = 8 dams, respectively). The gadolinium leakage into the placenta or fetus was calculated as the ratio of the Gd concentration of the placenta or fetus and the Gd concentration of maternal blood. (F) The expression levels of Tjs (claudin-5 and claudin-4) in placentas at E14.5. (G) The ultrastructure of TJs complexes expressed on the amniotic epithelium was visualized by SEM. (H) and (I) Semi-quantification of the Western blot results of claudin-4 and claudin-5 (F) in placentas at E14.5. (n = 7 dams, respectively). (J) The ultrastructure of TJs in placental syncytio trophoblast cells (SCTs) was observed by TEM. fNRBCs: fetal nucleated red blood cells. Endo f: fetal endothelial cells. MS: maternal blood sinus. SCT I with microvilli contacts with the MS directly. The yellow triangle indicates loosely bound Tjs or cracks. The blue triangle indicates the normal Tjs. Statistics were calculated by one-way ANOVA with Dunnett’s post hoc test for (C), (D), (E), (H) and (I). The statistical significance is denoted by ns, not significant; *P < 0.05; **P < 0.01. The graphs show the mean ± SEM

Article Snippet: Reagents VPA (Sigma-Aldrich, St. Louis, MO); RU486 (Selleck Chemicals, Shanghai, China); taprenepag, butaprost and linrodostat (MedChemExpress, Shanghai, China); and kynurenine (Aladdin, Shanghai, China).

Techniques: Concentration Assay, Expressing, Western Blot

Journal: Journal of neuroinflammation

Article Title: Taprenepag restores maternal-fetal interface homeostasis for the treatment of neurodevelopmental disorders.

doi: 10.1186/s12974-024-03300-7

Figure Lengend Snippet: Fig. 4 Taprenepag increased the number of TPH-2+ neurons and improved the development of TCAs in fetuses exposed to VPA. (A) Schematic diagram for the neuronal bodies and axons of TPH-2+ neurons and the development of Netrin-G1a+ TCAs and section positions of different slices. VPA-exposed pregnant mice received VPA at E12.5 and drug treatment (0.05 mg/kg RU486 or 0.5 mg/kg taprenepag) at E13.5. The sections were observed 24 h after administration. (B) and (C) The mean fluorescence intensity of TPH-2+ neuron body immunofluorescence staining in the MRN and TPH-2+ axons in MFB. (n = 5 dams, respectively). (D) Immunofluorescence staining of the neuron bodies and axons of TPH-2+ neurons and Netrin-G1a+ TCAs. Statistics were calculated by one-way ANOVA with Dunnett’s post hoc test for (B) and (C). Statistical significance was denoted by *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. The graphs show the mean ± SEM

Article Snippet: Reagents VPA (Sigma-Aldrich, St. Louis, MO); RU486 (Selleck Chemicals, Shanghai, China); taprenepag, butaprost and linrodostat (MedChemExpress, Shanghai, China); and kynurenine (Aladdin, Shanghai, China).

Techniques: Fluorescence, Immunofluorescence, Staining

Journal: Journal of neuroinflammation

Article Title: Taprenepag restores maternal-fetal interface homeostasis for the treatment of neurodevelopmental disorders.

doi: 10.1186/s12974-024-03300-7

Figure Lengend Snippet: Fig. 5 Taprenepag improved ASD-related behavioral abnormalities and damage to TPH-2+ neurons in offspring exposed to VPA. (A) Schematic dia gram of the implementation of the experimental plan. VPA-exposed pregnant mice received VPA at E12.5 and Tap treatment (0.5 mg/kg or 2.5 mg/kg) at E13.5. The fetal and placental experiments were carried out at E14.5. USV was conducted at P3-P11, regardless of gender. Behavioral evaluation for male mice began at P45 and was conducted under the following order: (open field, self-grooming behavior, marble burying and three-chamber social interaction assay). (B) The percentage of pregnant mice with any (at least one) fetal resorption event (%). (Control and VPA + Tap, n = 14 dams; VPA, n = 13 dams; VPA + RU486, n = 9 dams.) (C) The percentage of resorbed fetuses relative to total fetuses. (Control and VPA + Tap, n = 14 dams; VPA, n = 13 dams; VPA + RU486, n = 9 dams.) (D) The total calls for pups in 3 min in the isolation-induced distress vocalization assay. (n = 12 dams, respectively). (E) The cumu lative time spent in self-grooming in 10 min. (n = 12 dams, respectively). (F) The number of marbles buried in 15 min. (n = 12 dams, respectively). (G) For sociability testing, the time of tested mice spent in the Mouse chamber and Object chamber. (n = 12 dams, respectively). (H) For the social novelty testing, time of tested mice spent in the Familiar chamber and Unfamiliar chamber. (n = 12, respectively). (I) Immunofluorescence staining of TPH-2+ neurons and 5-HT in the RN at P55. (J) Schematic diagram of TPH-2+ neurons and 5-HT and the positions of sections. (K) and (L) The mean fluorescence intensity of im munofluorescence staining TPH-2+ and 5-HT in RN. (n = 5 dams, respectively). Statistics were calculated by two-tailed χ2 test for (B), one-way ANOVA with Dunnett’s post hoc test for (C), (E), (F), (K) and (L) and two-way ANOVA with Tukey’s post hoc test for (D), (G) and (H). Statistical significance was denoted by *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. The graphs show the mean ± SEM

Article Snippet: Reagents VPA (Sigma-Aldrich, St. Louis, MO); RU486 (Selleck Chemicals, Shanghai, China); taprenepag, butaprost and linrodostat (MedChemExpress, Shanghai, China); and kynurenine (Aladdin, Shanghai, China).

Techniques: Control, Isolation, Immunofluorescence, Staining, Fluorescence, Two Tailed Test

Journal: bioRxiv

Article Title: Pharmacological cAMP stimulation via prostaglandin receptors rescues ciliary defects in CEP290-deficient human and mouse models

doi: 10.1101/2023.10.06.561156

Figure Lengend Snippet: A. Detection of PTGER 2 (EP 2 ) mRNA in untreated control (C1, C3) and mutant (I26, E36, E14/E32) fibroblasts under serum starvation. B. Detection of EP 2 mRNA in control (C1, C3) and mutant (I26, E36, E14/E32) fibroblasts under serum starvation after 24 hours of exposure to either the solvent DMSO (-) or 0.2µM Taprenepag (+). C. Relative expression of PTGER 2 mRNA in control (C1, C3) and mutant (I26, E36, E14/E32) fibroblasts under serum starvation conditions with no treatment, or treatment with DMSO or Taprenepag in DMSO. The analysis was conducted using quantitative RT-PCR with GUSB and RPLP0 genes as reference genes. Bars represent the mean ± standard deviation from ≥ 2 independent replicates. Statistical analysis involved an ordinary two-way ANOVA followed by a Tukey’s multiple comparison test. Significant p-values are denoted as follows: **** for p < 0.0001, *** for p < 0.001, and * for p < 0.05.

Article Snippet: Following 24 hours in serum-free medium, cells were exposed to either 0.2µM of Taprenepag (Edelris, Lyon, France), in DMSO, or DMSO alone for an additional 24 hours before being harvested.

Techniques: Mutagenesis, Solvent, Expressing, Quantitative RT-PCR, Standard Deviation, Comparison

Journal: bioRxiv

Article Title: Pharmacological cAMP stimulation via prostaglandin receptors rescues ciliary defects in CEP290-deficient human and mouse models

doi: 10.1101/2023.10.06.561156

Figure Lengend Snippet: This figure illustrates the variation in intracellular cAMP concentration in both control (C1) and mutant (I26, E36, E14/E32) cells after different treatments, including DMSO (-), 0.2µM Taprenepag (T0.2), 2µM Taprenepag (T2), 2.5µM Forskolin (F2.5), and 25µM Forskolin (F25). The bars represent the mean values ± SEM from three independent experimental replicates. The units are represented as arbitrary units (A.U.). Statistical analysis involved an ordinary two-way ANOVA followed by Dunnett’s multiple comparison test. Significant p-values are denoted as follows: **** for p < 0.0001, *** for p < 0.001, ** for p < 0.01, * for p < 0.05, and ns for not significant.

Article Snippet: Following 24 hours in serum-free medium, cells were exposed to either 0.2µM of Taprenepag (Edelris, Lyon, France), in DMSO, or DMSO alone for an additional 24 hours before being harvested.

Techniques: Concentration Assay, Mutagenesis, Comparison

Journal: bioRxiv

Article Title: Pharmacological cAMP stimulation via prostaglandin receptors rescues ciliary defects in CEP290-deficient human and mouse models

doi: 10.1101/2023.10.06.561156

Figure Lengend Snippet: A. This panel displays representative images of cilia in control (C1) and mutant (I26, E36, E14/E32) fibroblasts. These cells were exposed to either DMSO, 0.2µM Taprenepag (TAP), or 2.5µM and 25µM Forskolin (FORSK). Red labeling represents ARL13B, marking the ciliary membrane, green labeling corresponds to Gamma-tubulin, indicating the basal body, and blue labeling is DAPI, marking the nuclei. Scale bars are provided for reference, with 20µm for the main images and 10µm for the inserts. B. Quantification of the percentage of ciliated cells in both control and mutant fibroblasts following exposure to DMSO, 0.2µM Taprenepag (T0.2µM), or 2.5µM and 25µM Forskolin (F2.5µM and F25µM, respectively). The data are presented in a boxplot graphical view. The horizontal line within the box represents the median, while the upper and lower limits of the box represent the 25th (Q1) and 75th (Q3) percentile values. Whiskers extending from the box represent the 10th and 90th percentiles. C. Quantification of the average cilia length after exposure to DMSO, 0.2µM Taprenepag, or 2.5µM and 25µM Forskolin. Each data point corresponds to a single cilium, with bars indicating the median values along with Q1 and Q3. Data presented in panel B and C were collected from three independent replicates, involving more than 250 cells. Statistical analysis was performed using an ordinary one-way ANOVA followed by Tukey’s multiple comparison test. Significant p-values are represented as follows: **** for p < 0.0001, *** for p < 0.001, ** for p < 0.01, * for p < 0.05, and ns for not significant.

Article Snippet: Following 24 hours in serum-free medium, cells were exposed to either 0.2µM of Taprenepag (Edelris, Lyon, France), in DMSO, or DMSO alone for an additional 24 hours before being harvested.

Techniques: Mutagenesis, Labeling, Membrane, Comparison

Journal: bioRxiv

Article Title: Pharmacological cAMP stimulation via prostaglandin receptors rescues ciliary defects in CEP290-deficient human and mouse models

doi: 10.1101/2023.10.06.561156

Figure Lengend Snippet: This figure illustrates the ciliary phenotype of control (C: pooled values of C1 and C3) and mutant (I26, E36) fibroblasts after 24 hours of serum starvation under “high-content” conditions (refer to Material & Methods for details). The cells underwent serum starvation, followed by a 24-hour exposure to either DMSO (-), 0.2µM Taprenepag, or 0.2µM Alprostadil, both diluted in DMSO. The values represented in the figure depict the difference between the average cilia length of cells treated with the drugs and the average cilia length of cells exposed to DMSO only, as determined by automatic analysis. Each bar corresponds to the mean ± SEM from three independent replicates. Statistical analysis was conducted using an ordinary two-way ANOVA, followed by a Tukey’s multiple comparison test for each cell line. Significant p-values are denoted as follows: **** for p < 0.0001, ** for p < 0.01, * for p < 0.05, and ns for not significant.

Article Snippet: Following 24 hours in serum-free medium, cells were exposed to either 0.2µM of Taprenepag (Edelris, Lyon, France), in DMSO, or DMSO alone for an additional 24 hours before being harvested.

Techniques: Mutagenesis, Comparison

Journal: bioRxiv

Article Title: Pharmacological cAMP stimulation via prostaglandin receptors rescues ciliary defects in CEP290-deficient human and mouse models

doi: 10.1101/2023.10.06.561156

Figure Lengend Snippet: Taprenepag concentration (ng/mL) over time post-injection in A) the plasma and B) the retina (dark) and vitreous humor (light grey) of WT mice. Bars represent the mean ± SEM from 4 mice. LD denotes the limit of detection.

Article Snippet: Following 24 hours in serum-free medium, cells were exposed to either 0.2µM of Taprenepag (Edelris, Lyon, France), in DMSO, or DMSO alone for an additional 24 hours before being harvested.

Techniques: Concentration Assay, Injection

Journal: bioRxiv

Article Title: Pharmacological cAMP stimulation via prostaglandin receptors rescues ciliary defects in CEP290-deficient human and mouse models

doi: 10.1101/2023.10.06.561156

Figure Lengend Snippet: A. Representative images of H&E retinal staining from P30 non-treated C57BL/6J and Cep290 del 36 /del 36 mice treated with vehicle (-) or 18 mg/kg Taprenepag (TAP 18mg/kg). Scale bar = 50µm. OS, outer segment; IS, inner segment; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer. B. Quantification of the Outer Nuclear Layer (ONL) & Inner Segment (IS) + Outer Segment (OS) thickness of the retina from P30 Cep290 del 36 /del 36 mice treated with vehicle (light grey) or 18 mg/kg Taprenepag (dark grey). Each point refers to the average of the layer thickness normalized by the total thickness of the retina for one eye. Bars correspond to the mean ± SEM from ≥ 5 animals. A Mann-Whitney U-test was performed, * indicates a p-value <0.05. C. Representative images of P30 Cep290 del 36 /del 36 mice retina following treatment with vehicle (-) or 18 mg/kg Taprenepag (TAP 18mg/kg). Rhodopsin labeling in green, S-opsin in red, and M-opsin in purple. Nuclei are stained with DAPI (Blue). Scale bar = 20µm. D. Quantification of the amount of Rhodopsin in the IS+OS from P30 Cep290 del 36 /del 36 mice treated with vehicle (light grey) or 18 mg/kg Taprenepag (dark grey). Each point refers to one field from one eye. Bars correspond to the mean ± SEM of 6 fields from ≥ 3 mice. A Mann-Whitney U-test was performed, *** indicates a p-value <0.001. E. Dark-adapted (Scotopic) ERG recordings in P30 Cep290 del 36 /del 36 mice after repeated intraperitoneal injections of 18mg/kg Taprenepag (dark grey) or vehicle (dotted light grey). Amplitude of the a-wave (Left) and B-wave (Right). Bars correspond to the mean ± SEM from 6 mice (left and right eyes). An ordinary two-way ANOVA was performed with Sidak’s multiple comparison test. P-values <0.01 and <0.05 are respectively indicated by ** and *, ns means no significance.

Article Snippet: Following 24 hours in serum-free medium, cells were exposed to either 0.2µM of Taprenepag (Edelris, Lyon, France), in DMSO, or DMSO alone for an additional 24 hours before being harvested.

Techniques: Staining, MANN-WHITNEY, Labeling, Comparison

Journal: Science Advances

Article Title: Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E 2 receptor EP2 subtype

doi: 10.1126/sciadv.abf1268

Figure Lengend Snippet: ( A ) Cryo-EM density of EP2-G s in complex with PGE 2 , EVA, or TAP. EP2, blue; Gα s , yellow; Gβ, pink; Gγ, cyan; Nb35, gray; PGE 2 , red; EVA, green; and TAP, orange. ( B ) Ribbon representation of the PGE 2 -EP2-G s complex. EP2, blue; Gα s , yellow; Gβ, pink; Gγ, cyan; Nb35, gray; and PGE 2 , red. ( C ) Comparison of the EP2-G s complex with the β2AR-G s complex [Protein Data Bank (PDB) ID: 3SN6] and the active EP3 structure (PDB ID: 6AK3). The orientations of H8 of both EP2 and EP3 are significantly different from the G s -coupled receptor β2AR. ( D ) Comparison of the EP2-G s complex with the β2AR-G s complex (PDB ID: 3SN6) and the inactive EP4 structure (PDB ID: 5YHL). The separation between TM3 and TM6 of the EP2-G s complex was larger than the inactive EP4 structure but significantly smaller than the β2AR-G s complex. ( E ) Comparison of the EP2-G s complex structure with the β2AR-G s complex structure (PDB ID: 3SN6). The α5 helix of the G s in the EP2-G s complex tilted 15° compared to that in the β2AR-G s complex.

Article Snippet: Compounds including PGE 2 (HY-101952), TAP (HY-14899), and EVA (HY-14839) were purchased from MedChemExpress.

Techniques: Cryo-EM Sample Prep, Comparison

Journal: Science Advances

Article Title: Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E 2 receptor EP2 subtype

doi: 10.1126/sciadv.abf1268

Figure Lengend Snippet: ( A ) Detail interactions of TAP (marine) with EP2 (orange) were shown. H-bonds were depicted as red dashed lines. ( B ) 2D representation of contacts between EP2 with the ligand TAP. The polar bonds were presented by red dotted lines. Residues F188 ECL2 and W186 ECL2 that were implicated in hydrophobic interactions with the region A subpocket were presented in green. T82 2.54 and S86 2.58 formed stronger H-bond engagements with the region B subpocket and were presented in blue. The hydrophobic contacts of EP2 with TAP were colored pink. ( C and D ) Effects of mutations of TAP contacting residues in ligand binding and G s signaling. The competitive binding curve of TAP toward EP2 was created using 3 H-PGE 2 as the isotope probe (C). Bars represent the differences in calculated potency of TAP (△pEC 50 ) for each mutation according to wild-type (WT) EP2. *** P < 0.0001 [one-way analysis of variance (ANOVA) compared with the response of WT] (D). See fig. S5 (E and F) for detailed statistical evaluation and fig. S4D for receptor expression levels. ( E ) Sequence alignment of prostonoid receptors. Note that the combination of F112 3.28 and L301 7.39 was only found in EP2, DP1, and FP; I85 2.57 , F119 3.35 , S305 7.43 , and S308 7.46 exhibited great diversity among prostonoid receptor families.

Article Snippet: Compounds including PGE 2 (HY-101952), TAP (HY-14899), and EVA (HY-14839) were purchased from MedChemExpress.

Techniques: Ligand Binding Assay, Binding Assay, Mutagenesis, Expressing, Sequencing

Journal: Science Advances

Article Title: Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E 2 receptor EP2 subtype

doi: 10.1126/sciadv.abf1268

Figure Lengend Snippet: ( A ) Plot of Cα distances of residues between TM3 and TM6 of EP2 in PGE2, EVA and TAP-bound complex structures, and structures of the active EP3 (PDB ID: 6AK3 and PDB ID: 6M9T), active β2AR (PDB ID: 3SN6), and inactive EP4 (PDB ID: 5YHL). ( B ) Sequence alignment of residues involving activation in prostaglandin E receptor subfamily members (EP1 to EP4) and β2AR. The residues involving EP2 activation and their counterparts in other receptors are highlighted in red or shaded with blue backgrounds. ( C ) Vertical cut-through view of EVA-bound EP2 in the EP2-G s complex structure. ( D ) Superimposition of EVA-bound EP2 with the active β2AR (PDB ID: 3SN6) aligned at the “IPF motif”. ( E ) The detailed interactions of upper parts of TM3-TM5-TM6-TM7 in the EVA-bound EP2-G s complex. ( F ) Binding of EVA induced the activation of EP2 that presumably started with the rotation of side chains of S86 2.58 and T82 2.54 by approximately 150° to form polar interactions with the hydroxyl groups of the E ring of PGE2 or the pyridine ring in the EVA (left). These conformational changes and the interaction between the EVA with the S305 7.43 and I309 7.47 caused a downshift of the TM7 and a larger separation between the S308 7.46 and the T82 2.54 (left). A close-up view of the structural alignment of the S/P 7.46 -T 2.54 interactions between the EP2-EVA structure and the inactive EP4 (PDB ID: 5YHL) structure, which indicated a separation between the TM2 and TM7, as well as the overall downward shift of TM7 (right).

Article Snippet: Compounds including PGE 2 (HY-101952), TAP (HY-14899), and EVA (HY-14839) were purchased from MedChemExpress.

Techniques: Sequencing, Activation Assay, Binding Assay