Article Figures & Data
Figures
- Fig. 1.
Deduced amino sequence of human prostanoid receptors, in alignment. Amino acid residues with 100% homology between all receptors are highlighted in green. Amino acid residues with complete homology, except for DP2, are highlighted in blue.
- Fig. 2.
Structures of agonists for prostanoid DP1 and DP2 receptors. PGD2, the most active natural agonist, is shown in the circle. Promotion of DP2-selectivity mainly involves alterations to C15; α indicates natural 2-series side-chain. a, ring system related to 6β-PGI1. b, PGI2 analog with unnatural ring chirality. c, EP1 and EP2 agonism retained. d, some EP2 agonism remains. e, PGH2 analog with unnatural ring chirality. f, 14-cis isomer is major component.
- Fig. 3.
Structures of representative DP1 and DP2 (CRTH2) antagonists.
- Fig. 4.
Structures of agonists for prostanoid EP receptor subtypes. PGE2, the most active natural agonist, is shown in the circle. 17-Phenyl PGE2 and sulprostone have modest EP1/EP3 and EP3/EP1 selectivities, respectively. CP-533536 and compound 9 are EP2 agonists with nonprostanoid structures. a, Belley et al. (2005). b, Shimazaki et al. (2000). c, Blovin et al. (2010).
- Fig. 5.
Structures of representative EP1, EP3, and EP4 receptor antagonists. Heterocycle substitution in DG-041 maintains high EP3 affinity (Hategan et al., 2009).a, Asada et al. (2010). ONO-AE3-240, T. Maruyama, personal communication.
- Fig. 6.
Structures of agonists for the prostanoid FP receptor and the corresponding prostamide F receptor. PGF2α potently activates both receptors, whereas its C1-ethanolamide activates only the prostamide F receptor. a, partial agonist.
- Fig. 7.
Structures of FP antagonists and the prostamide antagonist (AGN 211334).
- Fig. 8.
Structures of agonists for the prostanoid IP receptor. PGI2 (prostacyclin), the most active natural agonist, is shown in the circle. The diphenyl-heteroatomic unit critical to IP agonism in nonprostacyclin mimetics of prostacyclin is shown in blue. a, partial agonist. b, prodrug for MRE-269.
- Fig. 9.
Structures of IP receptor antagonists.
- Fig. 10.
Structures of agonists for the prostanoid TP receptor. TxA2 and PGH2, the most active natural agonists, are shown in the circle. Only structural alterations relative to PGH2 and TxA2 are illustrated in the figure. The vertical bracket indicates the presence of 2-series α- and ω-chains. a, partial agonist.
- Fig. 11.
Structures of representative antagonists for the prostanoid TP receptor.
Tables
Prostanoid Receptor Subtype Prostanoid Molecular Evolution Cluster G Protein Second Messenger DP1 1 Gs ↑ cAMP EP1 2 ↑ [Ca2+]i EP2 1 Gs ↑ cAMP EP3 3 Gi ↓ cAMP EP4 1 Gs ↑ cAMP FP 2 Gq ↑ [Ca2+]i PI turnover IP 1 Gs ↑ cAMP TP 2 Gq ↑ [Ca2+]i PI turnover DP1 Agonist Route Dose Species Experimental Model Indication Reference 572C85 192C86 Topical 2–250 μg Rabbit, cat Intraocular pressure Glaucoma Matsugi et al., 1995 AL-6598 Topical 0.01% Monkey Intraocular pressure Glaucoma Toris et al., 2006 BW 245C Intrathecal 83 ng/kg (IC50) Mouse Nociceptin-induced allodynia Chronic pain Minami et al., 1997 BW 245C Topical 2.5 μg Rabbit Intraocular pressure Glaucoma Goh et al., 1988 BW 245C Topical 50 μM Mouse Epicutaneous sensitization to OVA Atopic dermatitis Angeli et al., 2004 BW 245C Intratracheal 100 μM Mouse OVA-alum asthma Asthma Hammad et al., 2007 BW 245C 1–1000 nM Rat Cell/tissue culture Neurodegenerative diseases Liang et al., 2005b BW 245C In vitro+ (−/− DP1 mice) 0.05–5 μM Mouse Ischemia-reperfusion injury Cerebral ischemic disorders Saleem et al., 2007b BW 245C Topical 0.01–1% Rabbit Intraocular pressure Glaucoma Woodward et al., 1990 BW 245C AS 702224 Intracavernosal BW 245C, 59 nM; AS 702224, 29 nM (EC50 in isolated human tissue) Rabbit, rat, human cavernosal tissue Penile tumescence Erectile dysfunction Brugger et al., 2008 SQ-27986 Topical 2.5–25 μg Rabbit Intraocular pressure Glaucoma Woodward et al., 1993 SQ-27986 Topical 1–30 μg Monkey Intraocular pressure Glaucoma Crawford et al., 1992 TS-022 Topical 2.5 → 250 nM Mouse NC/Nga mice Atopic dermatitis Arai et al., 2007 AL-6598, 2-[[(2Z)-4-[(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3- hydroxypropyl]-3-hydroxycyclopentyl]-2-buten-1-yl]oxy]-1-methylethyl ester, acetic acid.
DP1 Antagonist Route Dose Species Experimental Model Indication Reference Laropiprant Oral 37.5 → 300 mg (human dose) Mice, humans NA-induced cutaneous vasodilation in mice Adjunctive therapy for dyslipidemia Cheng et al., 2006; Paolini et al., 2009 S-5751 Oral 30 mg/kg Sheep Ascaris suum-induced asthma asthma Shichijo et al., 2009 NA, nicotinic acid.
EP1 Antagonists Route Dose Species Experimental Model Indication Reference ONO-8711 Intravenous 1 and 3 mg/kg Rat Acetic acid-induced inflammation Bladder inflammation Ikeda et al., 2006 ONO-8711 Dietary 400 or 800 ppm Rat PhIP-induced breast cancer Breast cancer Kawamori et al., 2001a,b ONO-8711 Dietary 250, 500, 1000 ppm Mouse Azoxymethane-induced aberrant crypt foci, Min mice Colon cancer Watanabe et al., 1999 ONO-8713 Oral 20 mg/kg Mouse DNFB contact sensitivity Contact dermatitis Nagamachi et al., 2007 ONO-8713 Topical 50 μg Mouse UVB-induced inflammation and tumor formation Sunburn, skin cancer Tober et al., 2006 ONO-8713 Dietary 250, 500 1000 ppm Mouse Azoxymethane-induced aberrant crypt foci Colon cancer Watanabe et al., 2000 ONO-8713 Intraventricular 0–1–10 nM Mouse NMDA excitotoxicity Stroke Ahmad et al., 2006a ONO-8713 Intraperitoneal 10 mg/kg Mouse Cerebral artery occlusion Stroke Ahmad et al., 2006a ONO-8713 Intrathecal 1 or 10 nmol Mouse Neurochemical allodynia Pain Tsukamoto et al., 2010 PF-2907617-02 Intravenous 1 mg/kg Rat Balloon catheter-induced bladder outlet obstruction Overactive bladder syndrome Lee et al., 2007a,b SC-51089 Intraperitoneal 25 mg/kg Mice KMG4 tumor xenografts on SCID mice Glioma Matsuo et al., 2004 SC-51089 Intraperitoneal 10 mg/kg Rat Lithium-pilocarpine status epilepticus Epilepsy Pekcec et al., 2009 SC-51322 Oral 10 mg/kg Rat Spontaneously hypertensive rat Hypertension Guan et al., 2007 PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; SC-51089, dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-(1-oxo-3-(4-pyridinyl)propyl)hydrazide, monohydrochloride.
Agonist Route Dose Species Experimental Model Indication Reference AH 13205 Aerosol 0.1–3 nM Guinea pigs Histamine induced bronchoconstriction Asthma Nials et al., 1993 Butaprost Tissue culture vs. oxytocin 10−6 M infusion Human Isolated human uterine specimens from pregnant and nonpregnant donors Prevention of preterm labor; dysmenorrhoea Duckworth et al., 2002 Butaprost Topical (ocular) 0.1% Monkey Laser-induced glaucomatous monkey Glaucoma Nilsson et al., 2006 CP 533536 Local implant 10, 50, 100 mg/ml Dog Canine ulnar critical defect Fracture healing Paralkar et al., 2003 CP 533536 Topical (ocular) 0.01–0.1% Dog, monkey Laser-induced glaucomatous monkey Glaucoma Woodward and Chen, 2007 Agonist Route Dose Species Experimental Model Indication Reference MB 28767 Intravenous 2 pmol · kg−1 · min−1 Pig Occlusion/reperfusion Cardiac infarction Hohlfeld et al., 2000 MB 28767 Intracisternal 1 fg–30 ng per animal Mouse Naloxone-induced withdrawal jumping Opiate withdrawal syndrome Nakagawa et al., 1995 ONO-AE-248 Subcutaneous 10 μg/kg Mouse Ovalbumin induced asthma Asthma Kunikata et al., 2005 TEI-3356 Intravenous 1 μg · kg−1 · h−1 Rat Occlusion/reperfusion Cardiac infarction Zacharowski et al., 1999 TEI-3356, 5-(-7-hydroxy-6-(4-hydroxy-4-methyl-1-octenyl)bicyclo(3.3.0)oct-2-en-3-yl)pentanoic acid.
Antagonist Route Dose Species Experimental Model Indication Reference DG-041 Intravenous 10 mg/kg Rat Urinary bladder distension Overactive bladder Su et al., 2008a DG-041 Oral 0.1–100 mg/kg Rat Ex vivo platelet aggregation; bleeding time Atherothrombosis Singh et al., 2009 L-826266 Intraperiaqueductal grey 0.125 nM–0.5 nM Mouse Formalin induced hyperalgesia Pain Oliva et al., 2006 L-826266 Intraplantar 3–30 nmol Mouse Paw-licking Rheumatoid arthritis Kassuya et al., 2007 ONO-AE3-240 Subcutaneous 3.30 mg/kg Mouse HSV-1 inoculation Post-herpetic pain Takasaki et al., 2005 ONO-AE3-240 Subcutaneous 50 nmol/tumor Mouse Sarcoma 180 cell tumor Cancer Amano et al., 2003 HSV-1, Herpes simplex virus 1.
- TABLE 8
Potential therapeutic application of EP4 antagonists (inflammation/pain is reviewed in Jones et al., 2009)
Agonist Route Dose Species Experimental Model Indication Reference L 161982 Intravitreal injection 0.01–1 μM Rat O2-retinopathy laser induced choroidal neovascularization Age-related macular degeneration Yanni et al., 2009 ONO-AE2-227 In diet 100–400 ppm Mouse Azoxymethane induced aberrant crypt foci; min mouse Colon cancer Mutoh et al., 2002 ONO-AE3-208 Oral 10 mg/kg Mouse Injection of M26 cells Colon cancer Yang et al., 2006 Agonist Route Dose Species Experimental Model Indication Reference 3,7-Dithia PGE1 and its isopropyl ester Topical 0.01–0.1% Monkey “Glaucomatous” monkey intraocular pressure Glaucoma Woodward et al., 2009 4819-CD Subcutaneous 0.3 mg/kg Mouse Ischemia-reperfusion injury Myocardial infarction Xiao et al., 2004 AEI-734 Colitis Kabashima et al., 2002 AGN 205203 and its methyl ester Subcutaneous 3 mg/kg Mouse Dextran sodium sulfate colitis Colitis Jiang et al., 2007 CP-734432 Subcutaneous 0.3–3 mg/kg Rat Ovariectomized rats Osteoporosis Ke et al., 2006 ONO-4819 Subcutaneous 10, 30 μg/kg Rat Femoral drill-hole injury Bone fracture healing, osteoporosis Tanaka et al., 2004 ONO-4819 Subcutaneous 3, 30 μg/kg Rat Mechanical loading, to tibia Bone fracture, osteoporosis Hagino et al., 2005 ONO-4819 Intravenous 100 ng/kg Rat Ovariectomized rat Osteoporosis Yoshida et al., 2002 ONO-AE1-329 Intracolonic 25, 100 μg/kg Rat Dextran sodium sulfate colitis Colitis Nitta et al., 2002 ONO-AE1-329 Intravenous 1–10 μg/kg Rat Indomethacin-induced lesions NSAID-induced gastrointestinal lesions Kunikata et al., 2002 ONO-AE1-329 Intraperitoneal 0.1 mg/kg Rat Indomethacin-induced lesions NSAID-induced gastrointestinal lesions Hatazawa et al., 2006 ONO-AE1-329 Subcutaneous 0.1–1000 ng/g Rat Neonatal ductus arteriosus dilatation Premature birth Momma et al., 2005 ONO-AE1-329 Local gelatin plug 1 mg/ml Guinea pig Auditory brain stem response Sensorineural hearing loss Hori et al., 2009 ONO-AE1-329 Subcutaneous 0.05, 0.5 mg/kg 55 μg daily infusion per animal Mouse N2 receptor knockout mice Nephrogenic diabetes insipidus Li et al., 2009 ONO-AE1-329 Subcutaneous 100 μg/kg Mouse Anti-glomerular basement membrane antibody nephritis Glomerulonephritis Nagamatsu et al., 2006 ONO-AE1-329 Intravenous 1–10 μg/kg Rat Endotoxin Septicemia Sakamoto et al., 2004 PF-04475270 Topical 0.002–0.1 mg/ml Dog Normal dog intraocular pressure Glaucoma Prasanna et al., 2009 Antagonist Route Dose Species Experimental Model Indication Reference GR-32191 (vapiprost) Oral (drinking water) 1 mg · kg−1 · day−1 Mouse STZ diabetes Diabetic retinopathy Wright et al., 2009 KP-496 Intratracheal 30 and 100 μm/animal Rat Sephadex induced airway inflammation Asthma Ishimura et al., 2009 KP-496 Intranasal 0.003–0.05% Guinea pig Ovalbumin, Japanese cedar pollen allergy Allergic rhinitis Mizutani et al., 2008 ONO-3708 Intradermal 0.1 and 1 nmol/site Mouse TxA2-induced scratching Pruritus Andoh et al., 2007 S18886 (terutroban) Oral 10 and 30 mg/kg Rat Uninephrectomized obese Zucker rats Type 2 diabetes Sebeková et al., 2007 STZ, streptozotocin; ONO-3708, (1S-(1α,2β(Z),3α(S*),5α))-7-(3-((cyclopentylhydroxyacetyl)amino)-6,6-dimethylbicyclo(3.1.1)hept-2-yl)-5-heptenoic acid.
DP2 antagonist Route Dose Species Experimental Model Indication Reference mg/kg AM 156 Oral 10 Mouse Smoke exposure COPD Stebbins et al., 2010 Compound 23 Oral 10 Mouse Ovalbumin allergy Allergic rhinitis Stearns et al., 2009 Compound A Oral 10 Mouse FITC-cutaneous allergy Atopic dermatitis Boehme et al., 2009 Ramatroban Oral 5 Mouse Allergic (ovalbumin) eosinophilic airway inflammation Asthma Uller et al., 2007 Ramatroban Oral 30 Mouse Cry J1-induced pollinosis Allergic rhinitis Nomiya et al., 2008 TM-30089 Oral 5 Mouse Allergic (ovalbumin) eosinophilic airway inflammation Asthma Uller et al., 2007 AM 156, (2′-((cyclopropanecarbonylethylamino)methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)acetic acid; COPD, chronic obstructive pulmonary disease; FITC, fluorescein isothiocyanate.
