8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-[2-(furanylmethyl)thio]-1-oxopropyl]hydrazide (SC-51322): A potent PGE2 antagonist and analgesic

Hallinan, E. Ann; Stapelfeld, Awilda; Savage, Michael A.; Reichman, Melvin

doi:10.1016/0960-894x(94)80027-8

Cited by 67 publications

(18 citation statements)

References 15 publications

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“…The spontaneously hypertensive rat (SHR) is a well established model of hypertension (22). SC51322 is a selective and potent EP1 receptor antagonist, and was originally developed as an analgesic (17,23,24). The effect of SC51322 on blood pressure in SHRs was assessed using daily radiotelemetric recordings of mean arterial blood pressure (MAP).…”

Section: Resultsmentioning

confidence: 99%

“…Both EP1 receptor antagonists (16)(17)(18) and EP1 knockout mice exist, but have not been characterized in models of hypertension. While conventional targeting of the gene encoding EP1 in mice suggests a role for EP1 in maintaining basal blood pressure (19), interpretation of these data is complicated by the circumstance that the EP1 locus encompasses a second gene on the antiparallel strand, the serine/ threonine protein kinase N (PKN) (20).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Guan¹,

Zhang²,

Wu³

et al. 2007

J. Clin. Invest.

100

106

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Guan¹,

Zhang²,

Wu³

et al. 2007

J. Clin. Invest.

100

106

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“…To examine whether EP 1 receptors are involved in the inhibitory effects of PGE 2 , we used the selective EP 1 antagonist, SC‐51322, which is reported to possess a pA2 value of 8.1 ( 27), and is approximately three orders of magnitude more potent than its analogue SC‐19220. The inhibitory effects of PGE 2 (10 −6 M) on IPSCs were not affected by application of SC‐51322 (10 −6 M) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Prostaglandin E₂ Inhibits Spontaneous Inhibitory Postsynaptic Currents in Rat Supraoptic Neurones via Presynaptic EP Receptors

Ibrahim

Shibuya

Kabashima

et al. 1999

J Neuroendocrinology

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Prostaglandin E2 (PGE2) has been implicated in the excitatory regulation of magnocellular neurones in the supraoptic nucleus (SON). We have recently reported that PGE2 excited SON neurones by directly activating postsynaptic PGE2 receptors (EP receptors) of a subclass other than EP1-3, but did not affect excitatory postsynaptic currents (EPSCs). In the present study, we examined presynaptic effects of PGE2 on rat SON neurones by measuring spontaneous inhibitory postsynaptic currents (IPSCs) by a slice patch-clamp technique. PGE2 inhibited spontaneous IPSCs in a dose-dependent and reversible manner. PGE2 selectively suppressed the frequency of IPSCs without affecting the amplitude of IPSCs in the presence of tetrodotoxin, a blocker of Na+ channels, indicating that the effects were presynaptic. The inhibitory effects of PGE2 on the frequency of IPSCs were mimicked by the EP1/EP3 agonists, 17PT-PGE2 and sulprostone, and the EP2/EP3 agonist, misoprostol, whereas the EP2 agonist, butaprost, or the FP agonist, fluprostenol, had little effect. The effects of PGE2 on IPSCs were unaffected by the selective EP1 antagonist, SC-51322. They were unaffected also by antagonists of GABAB and alpha2 adrenergic receptors, which are present at presynaptic terminals of GABA neurones in the SON and cause suppression of spontaneous IPSCs. The inhibitor of PG synthesis, indomethacin, had little effect on spontaneous IPSCs and on the inhibitory effects of PGE2 as well as of the GABAB agonist, baclofen, and noradrenaline. These results suggest that PGE2 inhibits release of GABA from the GABAergic terminals innervating SON neurones by activating presynaptic EP receptors, presumably of the EP3 subclass, and that such a presynaptic mechanism may play a role in the excitatory regulation of SON neurones by PGE2.

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“…AGN 197727 is structurally identical to AGN 211377 except for the presence of a 2,3‐trans double bond in AGN 211377. The selective antagonists for DP1 receptors, BWA868C (16); EP1 receptors, SC‐51322 (17); FP receptors, AS‐604872 (18), and EP 4 receptors, GW 627368 (19) were custom synthesized at Target Molecules, Ltd. (Southampton, United Kingdom). The TP antagonist SQ 29548 (20), the TP/DP 2 antagonist BAY U3405 (21), and the DP 2 antagonist TM 30089 (22) were purchased from Cayman Chemical (Ann Arbor, MI, USA).…”

Section: Methodsmentioning

confidence: 99%

In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti‐inflammatory effects

Woodward

Wang

et al. 2016

FASEB j.

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The purpose of these studies was to test the hypothesis that a selected polypharmacological approach for treating the prostanoid-mediated component of inflammatory diseases would produce a therapeutic effect superior to global inhibition of prostaglandin (PG) biosynthesis by aspirin-like drugs. The compound studied was AGN 211377, which had been previously shown to produce a superior effect on cytokine release from human macrophages compared with cyclooxygenase (COX) inhibitors. AGN 211377 antagonizes prostanoid prostaglandin D (DP), DP, prostaglandin E (EP), EP, prostaglandin F, and thromboxane A receptors but not anti-inflammatory EP, prostaglandin I, or EP receptors. Established rodent models of ocular inflammatory diseases were used to determine therapeutic effects in living animals. The drugs were administered systemically after predetermination of their blood levels to ensure bioavailability at an appropriate dose level. Whereas compounds selective for a single prostanoid receptor typically exhibited modest but statistically significant inhibition, AGN 211377 profoundly inhibited S-antigen-induced uveitis and laser-induced retinal neovascularization. Consistent with previous polypharmacological studies on chemokine/cytokine release from human macrophages, the prostanoid EP receptor played a permissive role in suppressing neovascularization and inflammation in vivo Comparing AGN 211377 with a close structural congener lacking EP antagonism (AGN 197727), AGN 197727 was much less active than AGN 211377, but pronounced anti-inflammatory and angiostatic effects were achieved by adding the EP antagonist compound (SC-51322) to AGN 197727 in the systemic dosing regimen. Further, AGN 211377 produced superior anti-inflammatory activity compared with the nonsteroidal anti-inflammatory agent ketorolac. These results indicate the value of using a polypharmacological approach in the design of novel therapeutic agents in preference to compounds targeting a single receptor or enzyme. A compound such as AGN 211377 may represent more effective therapy than COX inhibitors in treating uveitis and ocular diseases where neovascularization is a significant part of the pathology.-Woodward, D. F., Wang, J. W., Ni, M., Bauer, A., Martos, J. L., Carling, R. W., Poloso, N. J. In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti-inflammatory effects.

show abstract

8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-[2-(furanylmethyl)thio]-1-oxopropyl]hydrazide (SC-51322): A potent PGE2 antagonist and analgesic

Cited by 67 publications

References 15 publications

Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Prostaglandin E₂ Inhibits Spontaneous Inhibitory Postsynaptic Currents in Rat Supraoptic Neurones via Presynaptic EP Receptors

In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti‐inflammatory effects

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8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid,2-[3-[2-(furanylmethyl)thio]-1-oxopropyl]hydrazide (SC-51322): A potent PGE2 antagonist and analgesic

Cited by 67 publications

References 15 publications

Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Prostaglandin E2 Inhibits Spontaneous Inhibitory Postsynaptic Currents in Rat Supraoptic Neurones via Presynaptic EP Receptors

In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti‐inflammatory effects

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Prostaglandin E₂ Inhibits Spontaneous Inhibitory Postsynaptic Currents in Rat Supraoptic Neurones via Presynaptic EP Receptors