Prostacyclin
From DrugPedia: A Wikipedia for Drug discovery
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| + | {{Drugbox | ||
| + | | IUPAC_name = (5Z)-5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S)-3-hydroxyoct-1-enyl]-3,3a,4,5,6,6a-hexahydrocyclopenta[d]furan-2-ylidene]pentanoic acid | ||
| + | | CAS_number = 35121-78-9 | ||
| + | | CAS_supplemental = | ||
| + | | ATC_suffix = | ||
| + | | ATC_supplemental = | ||
| + | | PubChem = 5282411 | ||
| + | | DrugBank = DB01240 | ||
| + | | ChemSpiderID = | ||
| + | | chemical_formula = C<sub>20</sub>H<sub>32</sub>O<sub>5</sub> | ||
| + | | molecular_weight = 352.47 | ||
| + | | smiles = CCCCCC(C=CC1C(CC2C1CC(=CCCCC(=O)O)O2)O)O | ||
| + | | synonyms = Vasocyclin | ||
| + | | density = | ||
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| + | | solubility = | ||
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| + | | protein_bound = | ||
| + | | metabolism = | ||
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| + | | pregnancy_category= | ||
| + | | dependency_liability = | ||
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| + | }} | ||
A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from PROSTAGLANDIN ENDOPEROXIDES in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension (HYPERTENSION, PULMONARY). | A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from PROSTAGLANDIN ENDOPEROXIDES in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension (HYPERTENSION, PULMONARY). | ||
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As a drug, it is also known as "epoprostenol".<ref>{{DorlandsDict|three/000036426|epoprostenol}}</ref> The terms are sometimes used interchangeably. <ref name="pmid1883670">{{cite journal |author=Kermode J, Butt W, Shann F |title=Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery |journal=British heart journal |volume=66 |issue=2 |pages=175–8 |year=1991 |month=August |pmid=1883670 |pmc=1024613 |doi= |url=http://heart.bmj.com/cgi/pmidlookup?view=long&pmid=1883670}}</ref> | As a drug, it is also known as "epoprostenol".<ref>{{DorlandsDict|three/000036426|epoprostenol}}</ref> The terms are sometimes used interchangeably. <ref name="pmid1883670">{{cite journal |author=Kermode J, Butt W, Shann F |title=Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery |journal=British heart journal |volume=66 |issue=2 |pages=175–8 |year=1991 |month=August |pmid=1883670 |pmc=1024613 |doi= |url=http://heart.bmj.com/cgi/pmidlookup?view=long&pmid=1883670}}</ref> | ||
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==General Properties== | ==General Properties== | ||
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<b>*Water Solubility</b> | <b>*Water Solubility</b> | ||
| + | ==Production== | ||
| + | [[Image:Eicosanoid synthesis.svg|thumb|left|360px|Eicosanoid synthesis. (Prostacyclin near bottom center.)]]It is produced in [[endothelium|endothelial]] [[cell (biology)|cell]]s from [[prostaglandin|prostaglandin H<sub>2</sub>]] (PGH<sub>2</sub>) by the action of the [[enzyme]] [[prostacyclin synthase]]. Although prostacyclin is considered an independent mediator, it is called '''PGI<sub>2</sub>''' (prostaglandin I<sub>2</sub>) in eicosanoid nomenclature, and is a member of the [[prostanoid]]s (together with the [[prostaglandin]]s and [[thromboxane]]). | ||
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| + | The series-3 prostaglandin PGH<sub>3</sub> also follows the prostacyclin synthase pathway, yielding another prostacyclin, '''PGI<sub>3</sub>'''.<ref>{{cite journal |author=Fischer S, Weber PC |title=Thromboxane (TX)A3 and prostaglandin (PG)I3 are formed in man after dietary eicosapentaenoic acid: identification and quantification by capillary gas chromatography-electron impact mass spectrometry |journal=Biomed. Mass Spectrom. |volume=12 |issue=9 |pages=470–6 |year=1985 |pmid=2996649 |doi=10.1002/bms.1200120905}}</ref> The unqualified term 'prostacyclin' usually refers to PGI<sub>2</sub>. PGI<sub>2</sub> is derived from the ω-6 [[arachidonic acid]]. PGI<sub>3</sub> is derived from the ω-3 [[eicosapentaenoic acid|EPA]]. | ||
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| + | ==Function== | ||
| + | Prostacyclin (PGI<sub>2</sub>) chiefly prevents formation of the [[platelet]] plug involved in primary [[hemostasis]] (a part of [[blood clot]] formation). It is also an effective [[vasodilator]]. Prostacyclin's interactions in contrast to [[thromboxane]] (TXA<sub>2</sub>), another eicosanoid, strongly suggest a mechanism of cardiovascular [[homeostasis]] between the two hormones in relation to [[Blood vessel|vascular]] damage. | ||
| + | |||
| + | ==Degradation== | ||
| + | Prostacyclin, which has a [[half-life]] of seconds, is broken down into 6-keto-PGF<sub>1</sub> which is a much weaker vasodilator. | ||
| + | |||
| + | ==Mode of action== | ||
| + | Prostacyclin (PGI<sub>2</sub>) is released by healthy endothelial cells and performs its function through a [[paracrine]] signaling cascade that involves [[G protein-coupled receptor]]s on nearby platelets and endothelial cells. The platelet Gs protein-coupled receptor ([[prostacyclin receptor]]) is activated when it binds to PGI<sub>2</sub>. This activation, in turn, signals adenylyl cyclase to produce [[cyclic adenosine monophosphate|cAMP]]. cAMP goes on to inhibit any undue platelet activation (in order to promote circulation) and also counteracts any increase in cytosolic calcium levels which would result from [[thromboxane A2]] (TXA<sub>2</sub>) binding (leading to platelet activation and subsequent [[coagulation]]). PGI<sub>2</sub> also binds to endothelial [[prostacyclin receptor]]s and in the same manner raise cAMP levels in the cytosol. This cAMP then goes on to activate [[protein kinase A]] (PKA). PKA then continues the cascade by phosphorylating and inhibiting [[myosin light-chain kinase]] which leads to [[smooth muscle]] relaxation and [[vasodilation]]. Notably, PGI<sub>2</sub> and TXA<sub>2</sub> work as physiological antagonists. | ||
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| + | ==Pharmacology== | ||
| + | Synthetic prostacyclin analogues ([[iloprost]], cisaprost) are used intravenously, subcutaneously or by inhalation: | ||
| + | * as a [[vasodilator]] in severe [[Raynaud's phenomenon]] or [[ischemia]] of a limb; | ||
| + | * in [[pulmonary hypertension]]. | ||
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| + | Its production is inhibited indirectly by [[Non-steroidal anti-inflammatory drug|NSAIDs]], which inhibit the [[cyclooxygenase]] enzymes COX1 and COX2. These convert [[arachidonic acid]] to [[prostaglandin H2]] (PGH<sub>2</sub>), the immediate precursor of prostacyclin. Since thromboxane (an [[eicosanoid]] stimulator of platelet aggregation ) is also downstream of COX enzymes, one would think that the effect of NSAIDs would balance out. However, prostacyclin concentrations recover much faster than thromboxane levels, so aspirin administration initially has little to no effect but eventually prevents platelet aggregation (the effect of prostaglandins predominates as they are regenerated). This is explained by understanding the cells that produce each molecule, TXA<sub>2</sub> and PGI<sub>2</sub>. Since PGI<sub>2</sub> is primarily produced in a nucleated endothelial cell the COX inhibition by NSAID can be overcome with time by increased COX gene activation and subsequent production of more COX enzymes to [[catalyze]] the formation of PGI<sub>2</sub>. In contrast, TXA<sub>2</sub> is primarily released by anucleated plateles which are unable to respond to NSAID COX inhibition with additional [[transcription]] of the COX gene because they lack [[DNA]] material necessary to perform such a task. This allows NSAIDs to result in PGI<sub>2</sub> dominance that promotes circulation and retards [[thrombosis]]. | ||
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| + | ==See also== | ||
| + | *[[Essential fatty acid]] | ||
| + | |||
| + | ==References== | ||
| + | {{Antithrombotics}} | ||
| + | {{PAH rx}} | ||
| + | {{Prostaglandins}} | ||
==External Links== | ==External Links== | ||
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[[Category:Hormones]] | [[Category:Hormones]] | ||
| + | [[Category:Prostaglandins]] | ||
| + | [[Category:Gilead Sciences]] | ||
[[Category:Prostaglandins]] | [[Category:Prostaglandins]] | ||
[[Category:Gilead Sciences]] | [[Category:Gilead Sciences]] | ||
Current revision
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| Prostacyclin
| |
| Systematic (IUPAC) name | |
| (5Z)-5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S)-3-hydroxyoct-1-enyl]-3,3a,4,5,6,6a-hexahydrocyclopenta[d]furan-2-ylidene]pentanoic acid | |
| Identifiers | |
| CAS number | |
| ATC code | ? |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C20H32O5 |
| Mol. mass | 352.47 |
| SMILES | & |
| Synonyms | Vasocyclin |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status | |
| Routes | ? |
A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from PROSTAGLANDIN ENDOPEROXIDES in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension (HYPERTENSION, PULMONARY). Prostacyclin (or PGI2) is a member of the family of lipid molecules known as eicosanoids.
As a drug, it is also known as "epoprostenol".<ref>Template:DorlandsDict</ref> The terms are sometimes used interchangeably. <ref name="pmid1883670">Kermode J, Butt W, Shann F (August 1991). "Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery". British heart journal 66 (2): 175–8. PMID 1883670. PMC:1024613.</ref>
Contents |
[edit] General Properties
*Molecular Weight
352.47
*Molecular Formula
C20H32O5
*IUPAC NAME
(5Z)-5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S)-3-hydroxyoct-1-enyl]-3,3a,4,5,6,6a-hexahydrocyclopenta[d]furan-2-ylidene]pentanoic acid
*Canonical Smiles
CCCCCC(C=CC1C(CC2C1CC(=CCCCC(=O)O)O2)O)O
*Isomeric Smiles
CCCCC[C@@H](C=C[C@H]1[C@@H](C[C@H]2[C@@H]1C/C(=C/CCCC(=O)O)/O2)O)O
[edit] PhysioChemical Properties
*Melting Point
*LogP
*Water Solubility
[edit] Production
The series-3 prostaglandin PGH3 also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI3.<ref>Fischer S, Weber PC (1985). "Thromboxane (TX)A3 and prostaglandin (PG)I3 are formed in man after dietary eicosapentaenoic acid: identification and quantification by capillary gas chromatography-electron impact mass spectrometry". Biomed. Mass Spectrom. 12 (9): 470–6. doi:. PMID 2996649.</ref> The unqualified term 'prostacyclin' usually refers to PGI2. PGI2 is derived from the ω-6 arachidonic acid. PGI3 is derived from the ω-3 EPA.
[edit] Function
Prostacyclin (PGI2) chiefly prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation). It is also an effective vasodilator. Prostacyclin's interactions in contrast to thromboxane (TXA2), another eicosanoid, strongly suggest a mechanism of cardiovascular homeostasis between the two hormones in relation to vascular damage.
[edit] Degradation
Prostacyclin, which has a half-life of seconds, is broken down into 6-keto-PGF1 which is a much weaker vasodilator.
[edit] Mode of action
Prostacyclin (PGI2) is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells. The platelet Gs protein-coupled receptor (prostacyclin receptor) is activated when it binds to PGI2. This activation, in turn, signals adenylyl cyclase to produce cAMP. cAMP goes on to inhibit any undue platelet activation (in order to promote circulation) and also counteracts any increase in cytosolic calcium levels which would result from thromboxane A2 (TXA2) binding (leading to platelet activation and subsequent coagulation). PGI2 also binds to endothelial prostacyclin receptors and in the same manner raise cAMP levels in the cytosol. This cAMP then goes on to activate protein kinase A (PKA). PKA then continues the cascade by phosphorylating and inhibiting myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation. Notably, PGI2 and TXA2 work as physiological antagonists.
[edit] Pharmacology
Synthetic prostacyclin analogues (iloprost, cisaprost) are used intravenously, subcutaneously or by inhalation:
- as a vasodilator in severe Raynaud's phenomenon or ischemia of a limb;
- in pulmonary hypertension.
Its production is inhibited indirectly by NSAIDs, which inhibit the cyclooxygenase enzymes COX1 and COX2. These convert arachidonic acid to prostaglandin H2 (PGH2), the immediate precursor of prostacyclin. Since thromboxane (an eicosanoid stimulator of platelet aggregation ) is also downstream of COX enzymes, one would think that the effect of NSAIDs would balance out. However, prostacyclin concentrations recover much faster than thromboxane levels, so aspirin administration initially has little to no effect but eventually prevents platelet aggregation (the effect of prostaglandins predominates as they are regenerated). This is explained by understanding the cells that produce each molecule, TXA2 and PGI2. Since PGI2 is primarily produced in a nucleated endothelial cell the COX inhibition by NSAID can be overcome with time by increased COX gene activation and subsequent production of more COX enzymes to catalyze the formation of PGI2. In contrast, TXA2 is primarily released by anucleated plateles which are unable to respond to NSAID COX inhibition with additional transcription of the COX gene because they lack DNA material necessary to perform such a task. This allows NSAIDs to result in PGI2 dominance that promotes circulation and retards thrombosis.
[edit] See also
[edit] References
Template:Antithrombotics Template:PAH rx Template:Prostaglandins
