Scholarly article on topic 'The Concise Guide to PHARMACOLOGY 2015/16: Nuclear hormone receptors'

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Academic research paper on topic "The Concise Guide to PHARMACOLOGY 2015/16: Nuclear hormone receptors"

THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Nuclear hormone receptors

Stephen PH Alexander1, John A Cidlowski2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators

1 School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK,

2 National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA,

3 School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK,

4 Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK,

5 Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK

Abstract

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13352/full. Nuclear hormone receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.

Conflict of interest

The authors state that there are no conflicts of interest to declare.

©2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Overview: Nuclear hormone receptors are specialised transcription factors with commonalities of sequence and structure, which bind as homo- or heterodimers to specific consensus sequences of DNA (response elements) in the promoter region of particular target genes. They regulate (either promoting or repressing) transcription of these target genes in response to a variety of endogenous ligands. Endogenous agonists are hydrophobic entities which, when bound to the receptor promote conformational changes in the receptor to allow recruitment (or dissociation) of protein partners, generating a large multiprotein complex.

Two major subclasses of nuclear receptors with identified endogenous agonists can be identified: steroid and non-steroid hormone receptors. Steroid hormone receptors function typically as dimeric entities and are thought to be resident outside the nucleus in the unliganded state in a complex with chaperone proteins, which are liberated upon agonist binding. Migration to the nucleus and interaction with other regulators of gene transcription, including RNA polymerase, acetyltransferases and deacetylases, allows gene transcription to be regulated. Non-steroid hormone receptors typically exhibit a greater distribution in the nucleus in the

unliganded state and interact with other nuclear receptors to form heterodimers, as well as with other regulators of gene transcription, leading to changes in gene transcription upon agonist binding.

Selectivity of gene regulation is brought about through interaction of nuclear receptors with particular consensus sequences of DNA, which are arranged typically as repeats or inverted palindromes to allow accumulation of multiple transcription factors in the promoter regions of genes.

Family structure

5958 1A. Thyroid hormone receptors

5959 1B. Retinoic acid receptors

5960 1C. Peroxisome proliferator-activated receptors

5961 1D. Rev-Erb receptors

5962 1F. Retinoic acid-related orphans

5963 1H. Liver X receptor-like receptors

5964 1I. Vitamin D receptor-like receptors

5965 2A. Hepatocyte nuclear factor-4 receptors

5966 2B. Retinoid X receptors

5967 2C. Testicular receptors

5968 2E. Tailless-like receptors

5969 2F. COUP-TF-like receptors

5970 3B. Estrogen-related receptors

5971 4A. Nerve growth factor IB-like receptors

5972 5A. Fushi tarazu F1-like receptors

5973 6A. Germ cell nuclear factor receptors

5974 0B. DAX-like receptors

5975 Steroid hormone receptors

5975 3A. Estrogen receptors

5976 3C. 3-Ketosteroid receptors

1A. Thyroid hormone receptors

Nuclear hormone receptors 1A. Thyroid hormone receptors

Overview: Thyroid hormone receptors (TRs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [41]) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (T4) and thyroid hormone (triiodothyronine). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or heterodimer with members of the retinoid X receptor family. NH-3 has been described as an antagonist at TRs with modest selectivity for TR| [111].

Nomenclature Thyroid hormone receptor-a Thyroid hormone receptor-|3

Systematic nomenclature NR1A1 NR1A2

HGNC, UniProt THRA, P10827 THRB, PI 0828

Rank order of potency triiodothyronine > T4 triiodothyronine > T4

Agonists dextrothyroxine [20] dextrothyroxine [20]

Selective agonists - sobetirome (pA'd 10.2) [27, 1 33]

Comments: An interaction with integrin aV|3 has been suggested to underlie plasma membrane localization of TRs and non-genomic signalling [9].One splice variant, TRa2, lacks a functional DNA-binding domain and appears to act as a transcription suppressor.

Although radioligand binding assays have been described for these receptors, the radioligands are not commercially available.

Further Reading

Bianco AC. (2011) Minireview: cracking the metabolic code for thyroid hormone signaling. Endocrinology 152: 3306-11 [PMID:21712363]

Brent GA. (2012) Mechanisms of thyroid hormone action. J. Clin. Invest. 122: 3035-43 [PMID:22945636]

Flamant F et al. (2006) International Union of Pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol. Rev. 58: 705-11 [PMID:17132849]

Pramfalk C etal. (2011) Role of thyroid receptor | in lipid metabolism. Biochim. Biophys. Acta 1812: 929-37 [PMID:21194564]

Sirakov M etal. (2011) The thyroid hormones and their nuclear receptors in the gut: from developmental biology to cancer. Biochim. Biophys. Acta 1812: 938-46 [PMID:21194566]

Tancevski I etal. (2011) Thyromimetics: a journey from bench to bed-side. Pharmacol. Ther. 131: 33-9 [PMID:21504761]

1B. Retinoic acid receptors

Nuclear hormone receptors 1B. Retinoic acid receptors

Overview: Retinoic acid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [46]) are nuclear hormone receptors of the NR1B family activated by the vitamin A-derived agonists tretinoin (ATRA) and alitretinoin, and the RAR-selective synthetic agonists TTNPB and adapalene. BMS493 is a family-selective antagonist [47].

Nomenclature Retinoic acid receptor-a Retinoic acid receptor-P Retinoic acid receptor-y

Systematic nomenclature NR1B1 NR1B2 NR1B3

HGNC, UniProt RARA, P10276 RARB P10826 RARG, PI 3631

Agonists tretinoin (pEC50 7.8) [26] tretinoin (pEC50 7.9) [26] tretinoin (pEC50 9.7) [26]

(Sub)family-selective agonists tazarotene (pEC50 7.2) [26] tazarotene (pEC50 9.1) [26], adapalene (pK 7.5) [25] tazarotene (pECso 7.4) [26], adapalene (pA'i 6.9) [25]

Selective agonists BMS753 (pK 8.7) [53], Ro 40-6055 (pKd 8.2) [33], tamibarotene (pIC50 6.9) [65, 108, 146] AC261066 (pEC50 7.9-8.1) [90], AC55649 (pEC50 6.5-7.3) [90] AHPN (piCj 7.1) [25]

Selective antagonists Ro 41-5253 (pIC50 6.3-7.2) [2, 70] - MM 11253 [77]

Comments: Ro 41-5253 has been suggested to be a PPARy agonist [131]. LE135 is an antagonist with selectivity for RARa and RAR| compared with RARy [85].

Further Reading

Bour G et al. (2007) Protein kinases and the proteasome join in the combinatorial control of transcription by nuclear retinoic acid receptors. Trends Cell Biol. 17: 302-9 [PMID:17467991] Duong V et al. (2011) The molecular physiology of nuclear retinoic acid receptors. From health to

disease. Biochim. Biophys. Acta 1812: 1023-31 [PMID:20970498] Germain P et al. (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol. Rev. 58: 712-25 [PMID:17132850]

Maden M. (2007) Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat. Rev. Neurosci. 8: 755-65 [PMID:17882253]

Mark M et al. (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annu. Rev. Pharmacol. Toxicol. 46: 451-80 [PMID:16402912]

1C. Peroxisome proliferator-activated receptors

Nuclear hormone receptors 1C. Peroxisome proliferator-activated receptors

Overview: Peroxisome proliferator-activated receptors (PPARs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [101]) are nuclear hormone receptors of the NR1C family, with diverse roles regulating lipid homeostasis, cellular differentiation, proliferation and the immune response. PPARs have many potential endogenous agonists [14, 101], including 15-deoxy-A12,14-PGJ2, prosta-

cyclin (PGI2), many fatty acids and their oxidation products, lysophosphatidic acid (LPA) [98], 13-HODE, 15S-HETE, Paz-PC, azelaoyl-PAF and leukotriene B4 (LTB4). Bezafibrate acts as a non-selective agonist for the PPAR family [159]. These receptors also bind hypolipidaemic drugs (PPARa) and anti-diabetic thiazolidinediones (PPARy), as well as many non-steroidal antiinflammatory drugs, such as sulindac and indomethacin. Once

activated by a ligand, the receptor forms a heterodimer with members of the retinoid X receptor family and can act as a transcription factor. Although radioligand binding assays have been described for all three receptors, the radioligands are not commercially available. Commonly, receptor occupancy studies are conducted using fluorescent ligands and truncated forms of the receptor limited to the ligand binding domain.

Nomenclature Peroxisome proliferator-activated receptor-a Peroxisome proliferator-activated receptor-ß/5 Peroxisome proliferator-activated receptor-y

Systematic nomenclature NR1C1 NR1C2 NR1C3

HGNC, UniProt PPARA, Q07869 PPARD, Q03181 PPARC, P 372 31

Agonists - - mesalazine (pICso 1.8) [126]

Selective agonists GW7647 (pEC50 8.2) [18, 19], CP-775146 (pEC50 7.3) [68], pirinixic acid (pEC50 5.3) [159], gemfibrozil (pEC50 4.2) [31], ciprofibrate GW0742X (pIC50 9) [50, 144], GW501516 (pEC50 9) [11 3] GW1929 (piCj 8.8) [18], bardoxolone (Partial agonist) (piCj 8) [153], rosiglitazone (pKd 7.4) [59, 81, 165], rosiglitazone (pK-t 6.9) [88], troglitazone (pICso 6.3) [59, 165], pioglitazone (plC50 6.2) [59, 129, 165], troglitazone (pKt 5.8) [8], ciglitazone (pECso 4.6) [59]

Selective antagonists GW6471 (pIC50 6.6) [162] GSK0660 (pIC50 6.5) [134] T0070907 (piCj 9) [78], GW9662 (Irreversible inhibition) (pICso 8.1) [79], CDDO-Me (pA'j 6.9) [153]

Comments: As with the estrogen receptor antagonists, many agents show tissue-selective efficacy (e.g. [13, 110, 125]). Agonists with mixed activity at PPARa and PPARy have also been described (e.g [35, 52, 163]).

Further Reading

HuangJV etal. (2012) PPAR-yas a therapeutic target in cardiovascular disease: evidence and uncertainty. J. Lipid Res. 53: 1738-54 [PMID:22685322] Michalik L etal. (2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated

receptors. Pharmacol. Rev. 58: 726-41 [PMID:17132851] Michalik L et al. (2008) PPARs Mediate Lipid Signaling in Inflammation and Cancer. PPAR Res 2008:

134059 [PMID:19125181] Peters JM etal. (2012) The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat. Rev. Cancer 12: 181-95 [PMID:22318237]

Pirat C et al. (2012) Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators. J. Med. Chem. 55: 4027-61 [PMID:22260081]

Varga T et al. (2011) PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim. Biophys. Acta 1812: 1007-22 [PMID:21382489]

Youssef J etal. (2011) Peroxisome proliferator-activated receptors and cancer: challenges and opportunities. Br. J. Pharmacol. 164: 68-82 [PMID:21449912]

1D. Rev-Erb receptors

Nuclear hormone receptors 1D. Rev-Erb receptors

Overview: Rev-erb receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7]) have yet to be officially paired with an endogenous ligand, but are thought to be activated by heme.

Nomenclature Rev-Erb-a Rev-Erb-ß

Systematic nomenclature NR1D1 NR1D2

HGNC, UniProt NR1D1, P20393 NR1D2, Q14995

Endogenous agonists heme (Selective) [122, 164] heme (Selective) [122, 164]

Selective agonists GSK4112 (pEC50 6.4) [51], GSK4112 (pIC50 5.6) [73] -

Selective antagonists SR8278 (pIC50 6.5) [73] -

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Duez H et al. (2009) Rev-erb-alpha: an integrator of circadian rhythms and metabolism. J. Appl.

Physiol. 107: 1972-80 [PMID:19696364] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704 [PMID:17132848]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiol-

ogy and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675] Phelan CA et al. (2010) Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of

nuclear receptor-co-repressor interaction. Nat. Struct. Mol. Biol. 17: 808-14 [PMID:20581824] Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

Yin L etal. (2010) Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal 8: e001 [PMID:20414452]

1F. Retinoic acid-related orphans

Nuclear hormone receptors 1F. Retinoic acid-related orphans

Overview: Retinoic acid receptor-related orphan receptors (ROR, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7]) have yet to be assigned a definitive endogenous ligand, although RORa may be synthesized with a 'captured' agonist such as cholesterol [66, 67].

Nomenclature RAR-related orphan receptor-a RAR-related orphan receptor-ß RAR-related orphan receptor-y

Systematic nomenclature NR1F1 NR1 F2 NR1F3

HGNC, UniProt RORA P35398 RORB Q92753 RORC, P51449

Endogenous agonists cholesterol (Selective) [67, 115] - -

Selective agonists 7-hydroxycholesterol [15], cholesterol sulphate [15, 67]

Comments: tretinoin shows selectivity for ROR| within the ROR family [139]. RORa has been suggested to be a nuclear receptor responding to melatonin [158]. Further Reading

Benoit G etal. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856]

1H. Liver X receptor-like receptors

Nuclear hormone receptors 1H. Liver X receptor-like receptors

Overview: Liver X and farnesoid X receptors (LXR and FXR, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [105]) are members of a steroid analogue-activated nuclear receptor subfamily, which form heterodimers with members of the retinoid X receptor family. Endogenous ligands for LXRs include hydroxycholesterols (OHC), while FXRs appear to be activated by bile acids.

Nomenclature Farnesoid X receptor Farnesoid X receptor-ß Liver X receptor-a Liver X receptor-ß

Systematic nomenclature NR1H4 NR1H5 NR1H3 NR1H2

HGNC, UniProt NR1H4, Q96RI1 NR1H5P, - NR1H3, Q13133 NR1H2, P55055

Potency order chenodeoxycholic acid lithocholic acid, deoxycholic acid [93, 116] 20S-hydroxycholesterol, 22R-hydroxycholesterol, 24(S)-hydroxycholesterol 25-hydroxycholesterol, 27-hydroxycholesterol [80] 20S-hydroxycholesterol, 22R-hydroxycholesterol, 24(S)-hydroxycholesterol > 25-hydroxycholesterol, 27-hydroxycholesterol [80]

Endogenous agonists - lanosterol (pEC50 6) [114]-Mouse - -

Selective agonists GW4064 (pEC50 7.8) [95], obeticholic acid (pEC50 7) [11 7], fexaramine (pEC50 6.6) [36] - -

Selective antagonists guggulsterone (pIC50 5.7-6) [161] - - -

Comments: T0901317 [123] and GW3965 [28] are synthetic agonists acting at both LXRa and LXR| with less than 10-fold selectivity.

Further Reading

A-González N et al. (2011) Liver X receptors as regulators of macrophage inflammatory and metabolic

pathways. Biochim. Biophys. Acta 1812: 982-94 [PMID:21193033] Calkin AC et al. (2010) Liver x receptor signaling pathways and atherosclerosis. Arterioscler. Thromb.

Vasc. Biol. 30: 1513-8 [PMID:20631351] Chen WD etal. (2011) Nuclear bile acid receptor FXR in the hepatic regeneration. Biochim. Biophys.

Acta 1812: 888-92 [PMID:21167938] Claudel T etal. (2011) Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis,

and gallstone disease. Biochim. Biophys. Acta 1812: 867-78 [PMID:21194565] El-Hajjaji FZ etal. (2011) Liver X receptors, lipids and their reproductive secrets in the male. Biochim.

Biophys. Acta 1812: 974-81 [PMID:21334438] Gadaleta RM et al. (2010) Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease. Biochim. Biophys. Acta 1801: 683-92 [PMID:20399894]

Gardmo C etal. (2011) Proteomics for the discovery of nuclear bile acid receptor FXR targets. Biochim.

Biophys. Acta 1812: 836-41 [PMID:21439373] Kemper JK. (2011) Regulation of FXR transcriptional activity in health and disease: Emerging roles of FXR cofactors and post-translational modifications. Biochim. Biophys. Acta 1812: 842-50 [PMID:21130162]

Matsubara T et al. (2013) FXR signaling in the enterohepatic system. Mol. Cell. Endocrinol. 368: 17-29 [PMID:22609541]

Moore DD et al. (2006) International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. Pharmacol. Rev. 58: 742-59 [PMID:17132852]

1I. Vitamin D receptor-like receptors

Nuclear hormone receptors 1I. Vitamin D receptor-like receptors

Overview: Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [105]) are members of the NR1I family of nuclear receptors, which form heterodimers with members of the retinoid X receptor family. PXR and CAR are activated by a range of exogenous compounds, with no established endogenous physiological agonists, although high concentrations of bile acids and bile pigments activate PXR and CAR [105].

Nomenclature Vitamin D receptor Pregnane X receptor Constitutive androstane receptor

Systematic nomenclature NR1I1 NR1I2 NR1I3

HGNC, UniProt VDR P11473 NR1I2 O75469 NR113, Q14994

Endogenous agonists 1,25-dihydroxyvitamin D3 (pKd 8.9-9.2) [12, 39] 1 7ß-estradiol (Selective) [64] -

Selective agonists seocalcitol (pKd 9.6) [29, 157], doxercalciferol hyperforin (pEC50 7.6) [106, 156], 5ß-pregnane-3,20-dione (pIC50 6.4) [64], lovastatin (pEC50 5.3-6) [82], rifampicin (pEC50 5.5-6) [16, 82] TCPOBOP (pEC50 7.7) [149] - Mouse, CITCO(pEC5o 7.3) [92]

Selective antagonists TEI-9647 (pIC50 8.2) [128] - Chicken, ZK159222 (pIC50 7.5) [42, 60] - -

Comments clotrimazole [107] and T0901 31 7 [69] although acting at other sites, function as antagonists of the constitutive androstane receptor.

Further Reading

Bikle DD. (2011) Vitamin D: an ancient hormone. Exp. Dermatol. 20: 7-13 [PMID:21197695] Campbell FC et al. (2010) The yin and yang of vitamin D receptor (VDR) signaling in neoplastic progression: operational networks and tissue-specific growth control. Biochem. Pharmacol. 79: 1-9 [PMID:19737544]

Chen Y et al. (2012) Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. Biochem. Pharmacol. 83: 1112-26 [PMID:22326308]

Cheng J et al. (2012) Pregnane X receptor as a target for treatment of inflammatory bowel disorders.

Trends Pharmacol. Sci. 33: 323-30 [PMID:22609277] Ihunnah CA et al. (2011) Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim. Biophys. Acta 1812: 956-63 [PMID:21295138]

Kachaylo EM et al. (2011) Constitutive androstane receptor (CAR) is a xenosensor and target for

therapy. Biochemistry Mosc. 76: 1087-97 [PMID:22098234] Moore DD et al. (2006) International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. Pharmacol. Rev. 58: 742-59 [PMID:17132852] Plum LA et al. (2010) Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov 9:

941-55 [PMID:21119732] Staudinger JL et al. (2013) Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver. DrugMetab. Rev. 45: 48-59 [PMID:23330541]

2A. Hepatocyte nuclear factor-4 receptors

Nuclear hormone receptors 2A. Hepatocyte nuclear factor-4 receptors

Overview: The nomenclature of hepatocyte nuclear factor-4 receptors is agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7]. While linoleic acid has been identified as the endogenous ligand for HNF4a its function remains ambiguous [167]. HNF4y has yet to be paired with an endogenous ligand.

Nomenclature Hepatocyte nuclear factor-4-a Hepatocyte nuclear factor-4-y

Systematic nomenclature NR2A1 NR2A2

HGNC, UniProt HNF4A, P41235 HNF4C, Q14541

Endogenous agonists linoleic acid (Selective) [167] -

Selective antagonists BI6015 [72] -

Comments HNF4a has constitutive transactivation activity [167] and binds DNA as a homodimer [63].

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704 [PMID:17132848]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiol-

ogy and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675] Hwang-Verslues WW et al. (2010) HNF4a-role in drug metabolism and potential drug target? Curr

Opin Pharmacol 10: 698-705 [PMID:20833107] Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

2B. Retinoid X receptors

Nuclear hormone receptors 2B. Retinoid X receptors

Overview: Retinoid X receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [45]) are NR2B family members activated by alitretinoin and the RXR-selective agonists bexarotene and LG100268, sometimes referred to as rexinoids. UVI3003 [109] and HX 531 [37] have been described as a pan-RXR antagonists. These receptors form RXR-RAR heterodimers and RXR-RXR homodimers [23, 97].

Nomenclature Retinoid X receptor-a Retinoid X receptor-ß Retinoid X receptor-y

Systematic nomenclature NR2B1 NR2B2 NR2B3

HGNC, UniProt RXRA, P19793 RXRB P28702 RXRG, P48443

(Sub)family-selective agonists bexarotene (pIC50 7.4) [1 7, 22, 146] bexarotene (pIC50 7.7) [1 7, 22, 146] bexarotene (plC50 7.5) [1 7, 22, 146]

Selective agonists CD3254 (pIC50 8.5) [48] - -

Further Reading

Bour G et al. (2007) Protein kinases and the proteasome join in the combinatorial control of transcription by nuclear retinoic acid receptors. Trends Cell Biol. 17: 302-9 [PMID:17467991] Duong V etal. (2011) The molecular physiology of nuclear retinoic acid receptors. From health to

disease. Biochim. Biophys. Acta 1812: 1023-31 [PMID:20970498] Germain P et al. (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol. Rev. 58: 760-72 [PMID:17132853] Lefebvre P et al. (2010) Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol. Metab. 21: 676-83 [PMID:20674387]

Maden M. (2007) Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat. Rev. Neurosci. 8: 755-65 [PMID:17882253]

Mark M et al. (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annu. Rev. Pharmacol. Toxicol. 46: 451-80 [PMID:16402912]

Pérez E et al. (2011) Modulation of RXR function through ligand design. Biochim Biophys Acta [PMID:21515403]

2C. Testicular receptors

Nuclear hormone receptors 2C. Testicular receptors

Overview: Testicular receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7]) have yet to be officially paired with an endogenous ligand, although testicular receptor 4 has been reported to respond to retinoids.

Nomenclature Testicular receptor 2 Testicular receptor 4

Systematic nomenclature NR2C1 NR2C2

HGNC, UniProt NR2C1, P13056 NR2C2, P49116

Endogenous agonists - retinol (Selective) [1 73], tretinoin (Selective) [1 73]

Comments Forms a heterodimer with TR4; gene disruption appears without effect on testicular development or function [1 35]. Forms a heterodimer with TR2.

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Duez H et al. (2009) Rev-erb-alpha: an integrator of circadian rhythms and metabolism. J. Appl.

Physiol. 107: 1972-80 [PMID:19696364] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704 [PMID:17132848]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675] Phelan CA et al. (2010) Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction. Nat. Struct. Mol. Biol. 17: 808-14 [PMID:20581824]

Schimmer BP et al. (2010) Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol. Endocrinol. 24: 1322-37 [PMID:20203099] Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

Yin L etal. (2010) Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm

and metabolism. Nucl Recept Signal 8: e001 [PMID:20414452] Zhang Y et al. (2011) Role of nuclear receptor SHP in metabolism and cancer. Biochim. Biophys. Acta

1812: 893-908 [PMID:20970497] Zhao Y etal. (2010) NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler. Thromb. Vasc. Biol. 30: 1535-41 [PMID:20631354]

2E. Tailless-like receptors

Nuclear hormone receptors 2E. Tailless-like receptors

Overview: Tailless-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7] ) have yet to be officially paired with an endogenous ligand.

Nomenclature TLX PNR

Systematic nomenclature NR2E1 NR2E3

HGNC, UniProt NR2E1, Q9Y466 NR2E3, Q9Y5X4

Comments Gene disruption is associated with abnormal brain development [76, 104]. -

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704 [PMID:17132848]

Gui H etal. (2011) A tale of tailless. Dev. Neurosci. 33: 1-13 [PMID:21124006]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675]

Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

2F. COUP-TF-like receptors

Nuclear hormone receptors 2F. COUP-TF-like receptors

Overview: COUP-TF-like receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7] ) have yet to be officially paired with an endogenous ligand.

Nomenclature Systematic nomenclature HGNC, UniProt Comments

COUP-TF1 NR2F1

NR2F1, P10589

Gene disruption is perinatally lethal [121].

COUP-TF2 NR2F2

NR2F2, P24468

Gene disruption is embryonically lethal [118].

V-erbA-related gene NR2F6

NR2F6 P10588

Gene disruption impairs CNS development [155].

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704 [PMID:17132848]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiol-

ogy and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675]

Lin FJ etal. (2011) Coup d'Etat: an orphan takes control. Endocr. Rev. 32: 404-21 [PMID:21257780]

Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

3B. Estrogen-related receptors

Nuclear hormone receptors 3B. Estrogen-related receptors

Overview: Estrogen-related receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7]) have yet to be officially paired with an endogenous ligand.

Nomenclature Estrogen-related receptor-a Estrogen-related receptor-P Estrogen-related receptor-y

Systematic nomenclature NR3B1 NR3B2 NR3B3

HGNC, UniProt ESRRA P11474 ESRRB O95718 ESRRC, P62508

Comments Activated by some dietary flavonoids [141 ]; activated by the syntheticagonist GSK4716 [1 76] and blocked by XCT790 [160]. May be activated by DY1 31 [166]. May be activated by DY1 31 [166].

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Deblois G et al. (2011) Functional and physiological genomics of estrogen-related receptors (ERRs)

in health and disease. Biochim. Biophys. Acta 1812: 1032-40 [PMID:21172432] Deblois G et al. (2013) Oestrogen-related receptors in breast cancer: control of cellular metabolism

and beyond. Nat. Rev. Cancer 13: 27-36 [PMID:23192231] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704

[PMID:17132848]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675] Hwang-Verslues WW et al. (2010) HNF4a-role in drug metabolism and potential drug target? Curr

Opin Pharmacol 10: 698-705 [PMID:20833107] Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

4A. Nerve growth factor IB-like receptors

Nuclear hormone receptors 4A. Nerve growth factor IB-like receptors

Overview: Nerve growth factor IB-like receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7] ) have yet to be officially paired with an endogenous ligand.

Nomenclature Nerve Growth factor IB Nuclear receptor related 1 Neuron-derived orphan receptor 1

Systematic nomenclature NR4A1 NR4A2 NR4A3

HGNC, UniProt NR4A1 P22736 NR4A2 P43354 NR4A3, Q92570

Comments An endogenous agonist, cytosporone B, has been described [168], although structural analysis and molecular modelling has not identified a ligand binding site [4, 40, 154].

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704 [PMID:17132848]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675] McMorrow JP etal. (2011) Inflammation: a role for NR4A orphan nuclear receptors? Biochem. Soc.

Trans. 39: 688-93 [PMID:21428963] Mohan HM etal. (2012) Molecular pathways: the role of NR4A orphan nuclear receptors in cancer.

Clin. Cancer Res. 18: 3223-8 [PMID:22566377] Pearen MA et al. (2010) Minireview: Nuclear hormone receptor 4A signaling: implications for

metabolic disease. Mol. Endocrinol. 24: 1891-903 [PMID:20392876] Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

Zhao Y etal. (2010) NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler. Thromb. Vasc. Biol. 30: 1535-41 [PMID:20631354] van Tiel CM et al. (2012) NR4All in the vessel wall. J. Steroid Biochem. Mol. Biol. 130: 186-93 [PMID:21277978]

5A. Fushi tarazu F1-like receptors

Nuclear hormone receptors 5A. Fushi tarazu F1-like receptors

Overview: Fushi tarazu Fl-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7] ) have yet to be officially paired with an endogenous ligand.

Nomenclature Steroidogenic factor 1 Liver receptor homolog-1

Systematic nomenclature NR5A1 NR5A2

HGNC, UniProt NR5A1 Q13285 NR5A2, 000482

Comments Reported to be inhibited by AC45594 [32] and SID7969543 [91]. -

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Budefeld T et al. (2012) Steroidogenic factor 1 and the central nervous system. J. Neuroendocrinol. 24:

225-35 [PMID:21668533] El-Khairi R etal. (2011) Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal

function. EndocrDev 20: 38-46 [PMID:21164257] Fernandez-Marcos PJ etal. (2011) Emerging actions of the nuclear receptor LRH-1 in the gut. Biochim.

Biophys. Acta 1812: 947-55 [PMID:21194563] Ferraz-de-Souza B etal. (2011) Steroidogenic factor-1 (SF-1, NR5A1) and human disease. Mol. Cell.

Endocrinol. 336: 198-205 [PMID:21078366] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704

[PMID:17132848]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675] Lazarus KA et al. (2012) Therapeutic potential of Liver Receptor Homolog-1 modulators. J. Steroid

Biochem. Mol. Biol. 130: 138-46 [PMID:22266285] Mlnynarczuk J et al. (2010) The role of the orphan receptor SF-1 in the development and function

of the ovary. Reprod Biol 10: 177-93 [PMID:21113200] Schimmer BP et al. (2010) Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol. Endocrinol. 24: 1322-37 [PMID:20203099] Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

6A. Germ cell nuclear factor receptors

Nuclear hormone receptors 6A. Germ cell nuclear factor receptors

Overview: Germ cell nuclear factor receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7]) have yet to be officially paired with an endogenous ligand.

Nomenclature Germ cell nuclear factor

Systematic nomenclature NR6A1

HGNC, UniProt NR6A1, Q15406

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704 [PMID:17132848]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675] Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

0B. DAX-like receptors

Nuclear hormone receptors 0B. DAX-like receptors

Overview: Dax-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [7]) have yet to be officially paired with an endogenous ligand.

Nomenclature Systematic nomenclature HGNC, UniProt

DAX1 NR0B1

NR0B1, P51843

SHP NR0B2

NR0B2, Q15466

Further Reading

Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798-836 [PMID:17132856] Chanda D et al. (2008) Molecular basis of endocrine regulation by orphan nuclear receptor Small

Heterodimer Partner. Endocr. J. 55: 253-68 [PMID:17984569] Ehrlund A et al. (2012) Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease. J. Steroid Biochem. Mol. Biol. 130: 169-79 [PMID:21550402]

El-Khairi R etal. (2011) Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal

function. EndocrDev 20: 38-46 [PMID:21164257] Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685-704

[PMID:17132848]

Huang P et al. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu. Rev. Physiol. 72: 247-72 [PMID:20148675] Mlnynarczuk J et al. (2010) The role of the orphan receptor SF-1 in the development and function

of the ovary. Reprod Biol 10: 177-93 [PMID:21113200] Sladek FM. (2011) What are nuclear receptor ligands? Mol. Cell. Endocrinol. 334: 3-13 [PMID:20615454]

Zhang Y et al. (2011) Role of nuclear receptor SHP in metabolism and cancer. Biochim. Biophys. Acta 1812: 893-908 [PMID:20970497]

Steroid hormone receptors

Nuclear hormone receptors Steroid hormone receptors

Overview: Steroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [30, 89]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17P-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). These receptors exist as dimers coupled with chaperone molecules (such as hsp90p ( HSP90AB1, P08238) and immunophilin FKBP52FKBP4, Q02790), which are shed on binding the steroid hormone. Although rapid signalling

phenomena are observed [84, 120], the principal signalling cascade appears to involve binding of the activated receptors to nuclear hormone response elements of the genome, with a 15-nucleotide consensus sequence AGAACAnnnTGTTCT (i.e. an inverted palindrome) as homo- or heterodimers. They also affect transcription by protein-protein interactions with other transcription factors, such as activator protein 1 (AP-1) and nuclear factor /cB (NF-/cB). Splice variants of each of these receptors can form functional or non-functional monomers that can dimerize to form functional or non-functional receptors. For example, alternative

splicing of PR mRNA produces A and B monomers that combine to produce functional AA, AB and BB receptors with distinct characteristics [150].

A 7TM receptor responsive to estrogen (GPER1, Q99527, also known as GPR30, see [119]) has been described. Human ortho-logues of 7TM 'membrane progestin receptors' (PAQR7, PAQR8 and PAQR5), initially discovered in fish [174, 175], appear to localize to intracellular membranes and respond to 'non-genomic' progesterone analogues independently of G proteins [137].

3A. Estrogen receptors

Nuclear hormone receptors Steroid hormone receptors 3A. Estrogen receptors

Overview: Estrogen receptor (ER) activity regulates diverse physiological processes via transcriptional modulation of target genes. The selection of target genes and the magnitude of the response, be it induction or repression, are determined by many factors, including the effect of the hormone ligand and DNA binding on ER structural conformation, and the local cellular regulatory environment. The cellular environment defines the specific complement of DNA enhancer and promoter elements present and the availability of coregulators to form functional transcription complexes. Together, these determinants control the resulting biological response.

Nomenclature Systematic nomenclature HGNC, UniProt Endogenous agonists Selective agonists

(Sub)family-selective antagonists Selective antagonists

Estrogen receptor-a NR3A1

ESR1 P03372

estriol (pK 8.7) [75], estrone (pKj 8.5) [75]

propylpyrazoletriol (pKj 9.6) [74, 1 38], ethinyl estradiol (pIC50 8.7) [62]

bazedoxifene (pIC50 7.6) [103]

clomiphene (pKj 8.9) [3], methyl-piperidino-pyrazole (pKj 8.6) [142]

Estrogen receptor-ß NR3A2

ESR2, Q92731

WAY200070 (pIC50 8.5-9) [94], diarylpropionitril (pKj 8.6) [100, 1 38], prinaberel (pIC50 8.3) [94]

bazedoxifene (pIC50 7.1) [103]

R,R-THC (pK 8.4) [99, 143], PHTPP (pKi 6.9) [1 72]

Comments: R,R-THC exhibits partial agonist activity at ERa

[99, 143]. Estrogen receptors may be blocked non-selectively by

tamoxifen and raloxifene and labelled by [3H]17|-estradiol and 3

[3H]tamoxifen. Many agents thought initially to beantagonists

at estrogen receptors appear to have tissue-specific efficacy (e.g. Tamoxifen is an antagonist at estrogen receptors in the breast, but is an agonist at estrogen receptors in the uterus), hence the descriptor SERM (selective estrogen receptor modulator) or

SnuRM (selective nuclear receptor modulator). Y134 has been suggested to be an ERa-selective estrogen receptor modulator [112].

3C. 3-Ketosteroid receptors

Nuclear hormone receptors Steroid hormone receptors 3C. 3-Ketosteroid receptors

Nomenclature Androgen receptor Glucocorticoid receptor Mineralocorticoid receptor Progesterone receptor

Systematic nomenclature NR3C4 NR3C1 NR3C2 NR3C3

HGNC, UniProt AR, P10275 NR3C1, P04150 NR3C2 P08235 PGR, P06401

Rank order of potency dihydrotestosterone testosterone cortisol, corticosterone 2> aldosterone, deoxycortisone [127] corticosterone, cortisol, aldosterone, progesterone [127] progesterone

Endogenous agonists dihydrotestosterone (p^d 9.3) [147] - aldosterone (Selective) (pIC50 9.8-10) [58, 127] progesterone (Selective) (pECso 8.8) [38]

Agonists methyltestosterone (Androgen receptor promoter activity in luciferase reporter assay) (pEC50 9.7) [1], danazol (p^ 8) [24] -Rat, ethylestrenol, nandrolone

Selective agonists testosterone propionate (p.Kj 9.6) [96], mibolerone (pIC50 9) [49], fluoxymesterone (p^ 8.2) [61], methyltrienolone (pEC50 <5) [152], dromostanolone propionate fluticasone propionate (pIC50 9.3) [11], clobetasol propionate (pK 9.2) [3], desoximetasone (pK 8.9) [3], fluorometholone (pKj 8.8) [3], flunisolide (pKi 8.6) [3], diflorasone diacetate (pKj 8.5) [3], fluocinolone acetonide (pIC50 8.5) [3], beclometasone (pK| 8.4) [3], methylprednisolone (pK| 8.3) [3], fluocinonide (pIC50 8.3) [3], betamethasone (pIC50 8.1) [3], budesonide (pEC50 7.9) [102], triamcinolone (pIC50 7.7) [87], ZK216348 (pIC50 7.7) [132], ciclesonide (pKi 7.4) [6], prednisone (pKi 6.3) [3], RU26988 - Unknown, RU28362, difluprednate [145], fluticasone medroxyprogesterone (Affinity at human PR-A) (pA'j 9.5) [1 70], ORG2058, levonorgestrel [10, 130]

(continued)

Nomenclature Androgen receptor Glucocorticoid receptor Mineralocorticoid receptor Progesterone receptor

Antagonists cyproterone acetate (pKj 7.8) [55] mifepristone (pKd 9.4) [57, 127] nimodipine (inhibition of aldosterone-induced luciferase activity in a reporter system driven by the mineralocorticoid receptor ligand binding domain) (pIC50 6.8) [34]

Selective antagonists bicalutamide (pKj 7.7) [71], PF0998425 (pIC50 7.1-7.5) [86], enzalutamide (pIC50 7.4) [148], nilutamide (pIC50 7.1-7.1) [136], hydroxyflutamide (pEC50 6.6) [152], galeterone (pIC50 6.4) [56], flutamide (Displacement of 3[H] testosterone from wild-type androgen receptors) (pKi 5.4) [151] onapristone (pIC50 7.6) [169], ZK112993 finerenone (pIC50 7.7) [21], eplerenone (pKi 6.9) [5], onapristone (pIC50 6.3) [169], RU28318, ZK112993 ulipristal acetate (pICso 9.7) [124], mifepristone (Mixed) (pA'j 9) [1 71], onapristone (pKj 7.7) [54], ZK112993

Labelled ligands [3 H]dihyd rotestosterone (Selective Agonist), [3 H]methyltrienolone (Selective Agonist), [3H]mibolerone (Agonist) [3H]dexamethasone (Agonist) [3H]aldosterone (Selective Agonist) (pKd 9.5-9.4) [44, 140] - Rat [3H]C)RG2058 (Selective Agonist)

Comments: [3H]dexamethasone also binds to MRin vitro. PR antagonists have been suggested to subdivide into Type I (e.g. onapristone) and Type II (e.g. ZK112993) groups. These groups appear to promote binding of PR to DNA with different efficacies and evoke distinct conformational changes in the receptor, leading to a transcription-neutral complex [43, 83]. Mutations in AR underlie testicular feminization and androgen insensibility syndromes, spinal and bulbar muscular atrophy (Kennedy's disease).

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