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 G_q/11 protein. EP₃ receptors can either couple negatively to adenylyl cyclase through binding to a G_i protein, or like EP₁, FP and TP receptors, via G_q/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 "Materials" section below.

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