Discovery of novel biaryl heterocyclic EP1 receptor antagonists

Hall, Adrian; Bit, Rino A.; Brown, Susan H.; Chaignot, Helene M.; Chessell, Iain P.; Coleman, Tanya; Giblin, Gerard M.P.; Hurst, David N.; Kilford, Ian R.; Lewell, Xiao Qing; Michel, Anton D.; Mohamed, Shiyam; Naylor, Alan; Novelli, Riccardo; Skinner, Lee Joan; Spalding, David J.; Tang, Sac P.; Wilson, Richard

doi:10.1016/j.bmcl.2006.02.014

Cited by 20 publications

(2 citation statements)

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“…Repetition of the experiments with 5610 À 2 M and 8610 À 2 M of 3 gave, separately, the same fit curve and rate constant. In fact, the experimental data indicated that the observed pseudo-second order rate constant (k obs ) was equal to the second-order rate constant (k 2 ); this is possible when g is zero in Eqn (1). It is appears, therefore, that the reaction is zero and second order with respect to 3 (NH-acid) and the sum of 1 and 2 (2b) (a þ b ¼ 2), respectively.…”

Section: Effect Of Concentrationmentioning

confidence: 95%

Theoretical, Kinetic and Mechanistic Studies of the Reaction between Dialkyl Acetylenedicarboxylates, Triphenylphosphine and Pyrrole in Organic Solvents

Shahraki

Habibi‐Khorassani

Ebrahimi

et al. 2012

Progress in Reaction Kinetics and Mechanism

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The kinetics of the reaction between triphenylphosphine, dialkyl acetylenedicarboxylates and pyrrole in dry organic solvents at different temperatures have been studied spectrophotometrically. The observed overall second rate constant (k 2 ) for reaction decreases with decreasing solvent dielectric constant and media temperature; k 2 follows the Arrhenius equation, and the overall reaction is first order in both the dialkyl acetylenedicarboxylate and triphenylphosphine concentrations. The proposed mechanism has been evaluated, and the activation parameters DG 6 ¼ , DS 6 ¼ and DH 6 ¼ for the first, rate-determining step, as an elementary reaction have been determined on the basis of Eyring equation. In addition, the Z-and E-isomers have been optimized at HF and B3LYP levels with the 6-311þþG** basis set; the more stable is the E-isomer, in agreement with experimental data. Furthermore, to better understand the intramolecular interactions, atoms in molecules (AIM) calculations and natural population analysis (NPA) methods have been carried out. The 1 H, 13 C, and 31 P NMR data of these ylides are consistent with results obtained from theoretical calculations.

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Section: Effect Of Concentrationmentioning

confidence: 95%

Theoretical, Kinetic and Mechanistic Studies of the Reaction between Dialkyl Acetylenedicarboxylates, Triphenylphosphine and Pyrrole in Organic Solvents

Shahraki

Habibi‐Khorassani

Ebrahimi

et al. 2012

Progress in Reaction Kinetics and Mechanism

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show abstract

“…Then, changes in intracellular calcium were detected as rapid changes in fluorescent signal measured at 485 nm excitation, 525 nm emission with a cutoff filter set at 515 nm using a Flex Station 3 multi-mode microplate reader. The baseline calcium signal was measured for 120 seconds followed injection of PGE 2 (Hall et al, 2006) and the test compounds at the same time and reading of any changes in the calcium signal for an additional 780 seconds. At the termination of the experiment all signals were baseline subtracted and the change in intracellular calcium was quantified as the area under the curve, measured by integration.…”

Section: Calcium Assaysmentioning

confidence: 99%

Neuroprotective effects of Ginkgolide B in focal cerebral ischemia through selective activation of prostaglandin E2 receptor EP4 and the downstream transactivation of epidermal growth factor receptor

Yang

Qiu

et al. 2021

Phytotherapy Research

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The present study was undertaken to identify whether prostaglandin E2 receptor is the potential receptor/binding site for Ginkgolide A, Ginkgolide B, Ginkgolide K, and Bilobalide, the four main ingredients of the Ginkgo biloba L., leaves. Using functional assays, we identified EP4, coupled with Gs protein, as a target of Ginkgolide B. In human neuroblastoma SH-SY5Y cells suffered from oxygen-glucose deprivation/ reperfusion, Ginkgolide B-activated PKA, Akt, and ERK1/2 as well as Src-mediated transactivation of epidermal growth factor receptor. These resulted in downstream signaling pathways, which enhanced cell survival and inhibited apoptosis. Knockdown of EP4 prevented Ginkgolide B-mediated Src, epidermal growth factor receptor (EGFR), Akt, and ERK1/2 phosphorylation and neuroprotective effects. Moreover, Src inhibitor prevented Ginkgolide B-mediated EGFR transactivation and the downstream Akt and ERK1/2 activation, while the phosphorylation of PKA induced by Ginkgolide B was not affected, indicating Ginkgolide B might transactivate EGFR in a ligand-independent manner. EP4 knockdown in a rat middle cerebral artery occlusion (MCAO) model prevented Ginkgolide B-mediated infarct size reduction and neurological assessment improvement. At the same time, the increased expressions of p-Akt, p-ERK1/2, p-PKA, p-Src, and p-EGFR and the deceased expression of cleaved capases-3 induced by Ginkgolide B in cerebral cortex were blocked due to EP4 knockdown. In conclusion, Ginkgolide B exerts neuroprotective effects in rat MCAO model through the activation of EP4 and the downstream transactivation of EGFR.

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