Prostanoid Receptors

Prostanoids comprise prostaglandins (PGs) and thromboxanes (Txs). Prostanoid receptors can be classified into five types on the basis of sensitivity to the five naturally-occurring ligands; PGD2, PGE2, PGF2, PGI2 and TxA2. These receptors are termed P receptors, with a preceding letter indicating the natural prostanoid to which each receptor is most sensitive - i.e. DP, EP, FP, IP and TP, respectively. Furthermore, EP receptors have been subdivided into four groups, EP1, EP2, EP3 and EP4, originally on the basis of their relative sensitivities to a range of selective agonists and antagonists, but subsequently, all have been cloned. It is important to appreciate that the recombinant EP4 receptor was originally identified as EP2, and all publications referring to recombinant EP2 receptors prior to 1995 actually refer to EP4 receptors. Evidence for a second subtype of DP receptor has been published, found in T-lymphocytes, and originally termed CRTH2. Interestingly, this receptor is unrelated to the other prostanoid receptors, being more similar to the FPR and BLT chemotactic receptors. Indomethacin acts as an agonist at this receptor, and the TP antagonist, ramatroban, has antagonist activity. This 'new' DP-receptor may now tentatively be termed DP2, with the existing DP receptor re-designated DP1, although this is yet to be made official. Although there is now a substantial body of evidence for subdivision within IP and TP receptors, this has yet to be formally accepted and incorporated within the classification. Isoprostanes, prostanoids synthesized through non-enzymatic conversion of arachidonic acid have been suggested to act at their own receptors, distinct from those for other prostanoids, but the evidence is ambiguous, and the case not proven. In addition, it has been suggested that certain prostaglandins ethanolamides (prostamides) also act at receptors distinct from the ‘classical’ prostanoid receptors, but definitive evidence is still awaited.

The original basis for the classification was functional, and there are many agonists selective for the various prostanoid receptors. However, few agonists are truly selective for one type of receptor over all of the others, exceptions being BW245C at DP (DP1) receptors, fluprostenol at FP receptors, and cicaprost at IP receptors. There are potent antagonists for DP, EP1, EP4 and TP receptors; EP3 antagonists are just emerging, but there are still no well characterized potent selective antagonists at EP2, FP or IP receptors.

Although it is now known that there are splice variants of FP, TP and EP1 receptors, they are particularly well established for EP3 receptors, where at least ten splice variants have been reported to date across a variety of species (four of which have been found in man). In all cases, the splicing occurs in the intracellular C-terminal region, and while there is no evidence that it affects ligand affinities, it does appear to influence the receptors’ coupling to particular signal transduction processes. The splice variant of the EP1 receptor is distinct, in that the splice region incorporates the sixth and seventh intracellular domains, and the resulting receptor does not appear to couple directly to any recognized signal transduction process.

Prostanoid-induced effects are mainly transduced through modulation of the activity of either adenylyl cyclase or inositol phospholipid hydrolysis and calcium mobilization. DP1, EP2, EP4 and IP receptors couple positively to adenylyl cyclase through binding to a Gq/11 protein. EP3 receptors can either couple negatively to adenylyl cyclase through binding to a Gi protein, or like EP1, FP and TP receptors, via Gq/11 binding to inositol phospholipid hydrolysis and calcium mobilization. IP receptors appear to be most unusual among the prostanoid receptors, and indeed among G protein-coupled receptors in general, in that the receptor protein requires isoprenylation in order to optimize agonist-induced activation.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Currently Accepted Name EP1 EP2 EP3 EP4
Alternate Name None None None None
Structural Information 402 aa (human) 358 aa (human) 4 splice variants: 390, 388, 365, 374 aa (human) 488 aa (human)
Subtype Selective Agonists 17-Ph-ω-PGE2
Iloprostb
Butaprost (B6309)
AH-13205 (A9102)
CP-533,536
ONO-AE1-259
SC-46275
GR63799
Sulprostonee (S8692)
ONO-AE-248
ONO-AE1-734
ONO-AE1-329
Subtype Selective Antagonists SC-1922 (S3065)
AH6809 (A1221)
SC-51809
AH6809d (A1221)
L-798,106 AH23848f (A8227)
L-161,982 (SML0690)
ONO-AE3-208
GW627368
Receptor Selective Agonists PGE2 (P5640)
PGE2 (P5640)
PGE2 (P5640)
Misoprostol (M6932)
PGE2 (P5640)
Receptor Selective Antagonists Not Known
Not Known
Not Known
Not Known
Signal Transduction Mechanisms Gq/11 (increase IP3/DAG) Gs (increase cAMP) Gq/11 (increase IP3/DAG)
Gi (cAMP modulation)
Gs (increase cAMP)
Radioligands of Choice [3H]-PGE2 [3H]-PGE2 [3H]-PGE2
[3H]-Sulprostone
[3H]-PGE2
Tissue Expression Kidney, myometrium, GI smooth muscle Myometrium, airway smooth muscle, GI smooth muscle Myometrium, kidney, GI mucosa Ductus arteriosus, kidney, lymphocytes, mononuclear cells
Physiological Function Modulation of pain, diuresis & natriuresis Control of uterine contractility Control of uterine contractility, natriuresis, GI cytoprotection Control of ductus, bone metabolism
Disease Relevance Inflammatory pain, diabetic nephropathy Pre-term labor Pre-term labor, gastric ulcer Patent ductus, colonic inflammation

 

 

Currently Accepted Name DPa FP IP TP
Alternate Name None None None None
Structural Information 359 aa (human) 358 aa (human) 386 aa (human) 343 aa (human)
Subtype Selective Agonists Not Known
Not Known
Not Known
AGN 192093
Subtype Selective Antagonists Not Known
Not Known
Not Known
Not Known
Receptor Selective Agonists PGD2 (P5172)
BW245C (B9305)
ZK 110841
RS 93520
SQ 27986
L-644,698
PGF2a (P0424)
Fluprostenol (F8549)
Cloprostenol (C6116)
Latanoprost (L1167)
PGI2 (P6188)
Cicaprost
Iloprostb
BMY 45778
Beraprost
ONO-1301 (O2264)
U-46619 (D8174)
STA2
I-BOP (SML0504)
AGN 192093
SQ 26655
Receptor Selective Antagonists BWA868C (B9180)
AH6809 (A1221)
S-5751
ZK 138,357
Not Known
Not Known
GR32191 (G5044)
SQ 29548 (S144)
BM 13505 (D7441)
EP092
L-655,240
ICI 192605 (I2536)
ONO 3708
BMS 180291
Ramatroban (R0531)
KW-3635
Signal Transduction Mechanisms Gs (increase cAMP) Gq/11 (increase IP3/DAG) Gs (increase cAMP)
Gq/11 (increase IP3/DAG)
Gq/11 (increase IP3/DAG)
Radioligands of Choice [3H]-PGD2 [3H]-PGF2a
[3H]-17-Phe-ω-PGF2a
[3H]-PGI2
[3H]-Iloprost
[3H]-U-46619
[3H]-SQ 29548
[125I]-BOP
Tissue Expression Blood platelets, myometrium, ciliary muscle, basophils Corpus luteum, myometrium, ciliary body Blood platelets, vascular smooth muscle, sensory nerves Blood platelets, vascular smooth muscle, airways smooth muscle
Physiological Function Regulation of sleep Luteolysis, labor Control of platelet, aggregation, vasodilatation, pain Control of platelet aggregation, vasoconstriction, bronchoconstriction
Disease Relevance Not Known Not Known Not Known Diabetic vascular occlusion

 

Footnotes

a) DP receptor may now be re-designated DP1, with CRTH2 re-designated as DP2.

b) Iloprost is a partial agonist at EP1 receptors, but is a potent full agonist at IP receptors. Sulprostone is more potent as an EP3 agonist.

c) Misoprostol is also an EP3 agonist.

d) Human EP2 receptors only; also antagonist at EP1 and DP receptors.

e) Sulprostone also has moderate EP1 agonistic activity.

f) AH23848 is also a potent TP receptor blocking drug.

 

Abbreviations

AGN 192093: (5Z,9a,11a,13E,15S)-Prosta-5,13-diene-1,9,11,15-tetrol-cyclic-9,11-carbonate
AH-13205: trans-2-(4-(1-Hydroxyhexyl)phenyl)-5-oxocyclopentaneheptanoic acid
AH-23848: [1a(Z),2b,5a]-(±)-7-[5-[[(1,1’-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid
AH-6809: 6-Isopropoxy-9-oxoxanthene-2-carboxylic acid
Beraprost: (rac-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-Tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butyrate)
BM 13505 (Daltroban): 4-(2-(4-Chlorobenzenesulfonylamino)ethyl)benzeneacetic acid
BMS 180291 (Ifetroban): 1S-(1a,2a,3a,4a)]-2-[[3-[4-[(+++Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid
BMY 45778: (3-(4,5-Diphenyl(2,4'-bioxazol)-5'-yl)phenoxy)acetic acid
1-BOP: [1S[1a,2a(Z),3b(1E,3S*),4a]]-7-[3-[3-Hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo- [2.2.1]hept-2-yl]5-heptanoic acid
BW 245C: 3-(3-Cyclohexyl-3-hydroxypropyl)-2,5-dioxoimidazolidine-4-heptanoic acid
BW A868C: 3-Benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin
CP-533,536: (3-{[4-Tert-butyl-benzyl(pyridine-3-sulfonyl)-amino-methyl}-phenoxy)-acetic acid
EP092: (1a,2b(Z),3a,4a)-(±)-7-(3-(1-(((Phenylamino)thioxomethyl)hydrazono)ethyl)bicyclo(2.2.1)hept-2-yl)-5-heptenoic acid
GR 32191: (4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-Biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid
GR 63799: 7-(3-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl)-,4-(benzoylamino)phenyl ester,(1R-(1a(Z),2b(R*),3a))-4-heptenoic acid
GW 627368: (N-{2-[4-(4,9-Diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-acetyl}benzenesulphonamide)
ICI 192605: (4Z)-rel-6-[(2R,4R,5S)-2-(2-Chlorophenyl)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl]-4-hexenoic acid
KW-3635: Sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate monohydrate
L-161,982: [4’-[3-Butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]
L-644,698: ±(4-(3-(3-Hydroxyoctyl)-4-oxo-2-thiozolidinyl)propyl) benzoic acid
L-655,240: 3-(1-(4-Chlorobenzyl)-5-fluoro-3-methylindol-2-yl)-2,2-dimethylpropanoic acid
L-798,106: 5-Bromo-2-methoxy-N-[3-2-(naphthalen-2-yl-methylphenyl)-acryloyl]-benzenesulphonamide
ONO-1301: [7,8-dihydro-5-[(E)-[[a-(3-pyridyl)benzylidene]-aminooxy]ethyl]-1-naphtyloxy]acetic acid
ONO-3708: (1S-(1-a,2-b(Z),3-a(S*),5-a))-7-(3-((Cyclopentylhydroxyacetyl)amino)-6,6-dimethylbicyclo(3.1.1)hept-2-yl)-5-heptenoic acid
ONO-AE1-259: (16S-9-Deoxy-9β-chloro-15-deoxy-16-hydroxy-17,17-propano-19,20-didehydro PGE-2)
ONO-AE1-329: (16-(3-Methoxymethyl)phenyl-omega-tetranor-3,7-dithia PGE-1)
ONO-AE1-734: Methyl-7-[(1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-4-(m-methoxymethylphenyl)-1-butenyl]-5-oxocyclopenthl]-5-thiaheptanoate
ONO-AE3-208: 4-{4-Cyano-2-[2-(-fluoronaphthalen-1-yl)proprionylamino] phenyl}butyric acid
Ramatroban: (+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid
RS 93520: (4Z)-4-[(1R,2R,3S,6R)-2-[(3S)-3-Cyclohexyl-3-hydroxy-1-propynyl]-3-hydroxybicyclo[4.2.0]oct-7-ylidene]butanoic acid
S-5751: ((Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid)
SC 19220: 1-Acetyl-2-[8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl]hydrazine
SC 46275: Methyl-7-(2b-(6-(1-cyclopentyl-yl)-4R-hydroxy-4-methyl-1E,5E-hexadienyl)-3a-hydroxy-5-oxo-1R,1a-cyclopentyl)-4Z-heptenoate
SC 51809: (8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride)
SQ 26655: 9-alpha,11alpha-epoxy-10a-homo-15S-hydroxy-prosta-5Z,13E-dienoic acid
SQ 27986: 7-(3-(3-Cyclohexyl-3-hydroxy-1-propenyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-h eptenoic acid
SQ 29548: 7-(3-((2-((Phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid
STA2: (5Z)-7-[(1S,2R,3R,5S)-3-[(1E,3S)-3-Hydroxy-1-octenyl]-6-thiabicyclo[3.1.1]hept-2-yl]-5-heptenoic acid
U-46619: (5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3-Hydroxy-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid
ZK 110841: 9-Deoxy-9-chloro-16,17,18,19,20-pentanor-15-cyclohexyl- PGF 2a
ZK 138,357: (5Z)-7-[(2RS,4S,5S)-2-(2-chlorophenyl)-5-[(1E)-(3RS)-3-hydroxy-3-cyclohexyl-1-propenyl]-1,3-dioxolan-4-yl]-5-heptanoic acid

 

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References