The Concise Guide to PHARMACOLOGY 2013/14: nuclear hormone receptors.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 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.12444/full. Nuclear hormone receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. 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 the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

An Introduction to Nuclear Hormone Receptors

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 hormone 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 hormone 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 hormone 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.

Nomenclature	Thyroid hormone receptor-α	Thyroid hormone receptor-β
Systematic nomenclature	NR1A1	NR1A2
HGNC, UniProt	THRA, P10827	THRB, P10828
Rank order of potency	T3 > T4	T3 > T4
Selective agonists (pKi)	–	GC-1 (pKd 10.17) 2,5

Nomenclature	Retinoic acid receptor-α	Retinoic acid receptor-β	Retinoic acid receptor-γ
Systematic nomenclature	NR1B1	NR1B2	NR1B3
HGNC, UniProt	RARA, P10276	RARB, P10826	RARG, P13631
Selective agonists (pKi)	Ro 40-6055 7,11,18, BMS753 (8.7) 10	AC261066 (pEC50 7.9 – 8.1) 15, AC55649 (pEC50 6.5 – 7.3) 15	AHPN 16
Selective antagonists (pKi)	Ro 41-5253 (pIC50 6.3 – 7.2) 6,12	–	MM 11253 13

Nomenclature	Peroxisome proliferator-activated receptor-α	Peroxisome proliferator-activated receptor-β/δ	Peroxisome proliferator-activated receptor-γ
Systematic nomenclature	NR1C1	NR1C2	NR1C3
HGNC, UniProt	PPARA, Q07869	PPARD, Q03181	PPARG, P37231
Selective agonists (pKi)	ciprofibrate, GW7647 (pEC50 8.2) 22,23, CP-775146 (pEC50 7.3) 28, pirinixic acid (pEC50 5.3) 41	GW501516 (pEC50 9.0) 35, GW0742X (pIC50 9.0) 25,39	rosiglitazone (pKd 7.4) 27,31,44, GW1929 (8.8) 22, CDDO (Partial agonist) (8.0) 40, troglitazone (5.8) 19, ciglitazone (pEC50 4.6) 27, troglitazone (pIC50 6.3) 27,44, pioglitazone (pIC50 6.2) 27,37,44
Selective antagonists (pKi)	GW6471 (pIC50 6.6) 42	GSK0660 (pIC50 6.5) 38	T0070907 (9.0) 29, CDDO-Me (6.9) 40, GW9662 (Irreversible inhibition) (pIC50 8.1) 30

Nomenclature	Rev-Erb-α	Rev-Erb-β
Systematic nomenclature	NR1D1	NR1D2
HGNC, UniProt	NR1D1, P20393	NR1D2, Q14995
Endogenous agonists (pKi)	heme (Selective) 48,49	heme (Selective) 48,49
Selective agonists (pKi)	GSK4112 (pEC50 6.4) 46, GSK4112 (pIC50 5.6) 47	–
Selective antagonists (pKi)	SR8278 (pIC50 6.5) 47	–

Nomenclature	RAR-related orphan receptor-α	RAR-related orphan receptor-β	RAR-related orphan receptor-γ
Systematic nomenclature	NR1F1	NR1F2	NR1F3
HGNC, UniProt	RORA, P35398	RORB, Q92753	RORC, P51449
Endogenous agonists (pKi)	cholesterol (Selective) 53,54	–	–
Selective agonists (pKi)	7-hydroxycholesterol 51, cholesterol sulphate 51,53	–	–

Nomenclature	Farnesoid X receptor	Farnesoid X receptor-β	Liver X receptor-α	Liver X receptor-β
Systematic nomenclature	NR1H4	NR1H5	NR1H3	NR1H2
HGNC, UniProt	NR1H4, Q96RI1	NR1H5P, -	NR1H3, Q13133	NR1H2, P55055
Potency order	chenodeoxycholic acid > lithocholic acid, deoxycholic acid 60,64	–	20S-hydroxycholesterol, 22R-hydroxycholesterol, 24(S)-hydroxycholesterol > 25-hydroxycholesterol, 27-hydroxycholesterol 59	20S-hydroxycholesterol, 22R-hydroxycholesterol, 24(S)-hydroxycholesterol > 25-hydroxycholesterol, 27-hydroxycholesterol 59
Selective agonists (pKi)	GW4064 (pEC50 7.8) 61, ECDCA (pEC50 7.0) 65, fexaramine (pEC50 6.6) 58	–	–	–
Selective antagonists (pKi)	guggulsterone (pIC50 5.7 – 6.0) 67	–	–	–
Endogenous agonists (pKi)	–	lanosterol (pEC50 6.0 - Mouse) 63	–	–

Nomenclature	Vitamin D receptor	Pregnane X receptor	Constitutive androstane receptor
Systematic nomenclature	NR1I1	NR1I2	NR1I3
HGNC, UniProt	VDR, P11473	NR1I2, O75469	NR1I3, Q14994
Endogenous agonists (pKi)	1,25-dihydroxyvitamin D3 (pKd 8.9 – 9.2) 68,71	17β-estradiol (Selective) 74	–
Selective agonists (pKi)	EB1089 (pKd 9.57) 70,84	hyperforin (pEC50 7.6) 80,83, rifampicin (pEC50 5.5 – 6.0) 69,76, lovastatin (pEC50 5.3 – 6.0) 76, pregnanedione (pIC50 6.4) 74	TCPOBOP (pEC50 7.7 - Mouse) 82, CITCO (pEC50 7.3) 77
Selective antagonists (pKi)	TEI-9647 78, ZK159222 (pIC50 7.5) 72,73	–	–
Comment	–	–	clotrimazole 81 and T0901317 75 although acting at other sites, function as antagonists of the constitutive androstane receptor

Nomenclature	Hepatocyte nuclear factor-4-α	Hepatocyte nuclear factor-4-γ
Systematic nomenclature	NR2A1	NR2A2
HGNC, UniProt	HNF4A, P41235	HNF4G, Q14541
Endogenous agonists (pKi)	linoleic acid (Selective) 87	–
Selective antagonists (pKi)	BI6015 86	–

Nomenclature	Retinoid X receptor-α	Retinoid X receptor-β	Retinoid X receptor-γ
Systematic nomenclature	NR2B1	NR2B2	NR2B3
HGNC, UniProt	RXRA, P19793	RXRB, P28702	RXRG, P48443
Selective agonists (pKi)	CD3254 (pIC50 8.5) 91	–	–

Nomenclature	Testicular receptor 2	Testicular receptor 4
Systematic nomenclature	NR2C1	NR2C2
HGNC, UniProt	NR2C1, P13056	NR2C2, P49116
Endogenous agonists (pKi)	–	all-trans-retinoic acid (Selective) 96, retinol (Selective) 96
Comment	Forms a heterodimer with TR4; gene disruption appears without effect on testicular development or function 95	Forms a heterodimer with TR2

Nomenclature	TLX	PNR
Systematic nomenclature	NR2E1	NR2E3
HGNC, UniProt	NR2E1, Q9Y466	NR2E3, Q9Y5X4
Comment	Gene disruption is associated with abnormal brain development 98,99	–

Nomenclature	COUP-TF1	COUP-TF2	V-erbA-related gene
Systematic nomenclature	NR2F1	NR2F2	NR2F6
HGNC, UniProt	NR2F1, P10589	NR2F2, P24468	NR2F6, P10588
Comment	Gene disruption is perinatally lethal 102	Gene disruption is embryonically lethal 101	Gene disruption impairs CNS development 103

Nomenclature	Estrogen-related receptor-α	Estrogen-related receptor-β	Estrogen-related receptor-γ
Systematic nomenclature	NR3B1	NR3B2	NR3B3
HGNC, UniProt	ESRRA, P11474	ESRRB, O95718	ESRRG, P62508
Comment	Activated by some dietary flavonoids 105; activated by the synthetic agonist GSK4716 108 and blocked by XCT790 106	May be activated by DY131 107	May be activated by DY131 107

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
Comment	An endogenous agonist, cytosporone B, has been described 113, although structural analysis and molecular modelling has not identified a ligand binding site 109,111,112	–	–

Nomenclature	Steroidogenic factor 1	Liver receptor homolog-1
Systematic nomenclature	NR5A1	NR5A2
HGNC, UniProt	NR5A1, Q13285	NR5A2, O00482
Comment	Reported to be inhibited by AC45594 115 and SID7969543 116	–

Nomenclature	Germ cell nuclear factor
Systematic nomenclature	NR6A1
HGNC, UniProt	NR6A1, Q15406

Nomenclature	DAX1	SHP
Systematic nomenclature	NR0B1	NR0B2
HGNC, UniProt	NR0B1, P51843	NR0B2, Q15466

Nomenclature	Estrogen receptor-α	Estrogen receptor-β
Systematic nomenclature	NR3A1	NR3A2
HGNC, UniProt	ESR1, P03372	ESR2, Q92731
Selective agonists (pKi)	PPT (9.64) 128,143	ERB 041 133, diarylpropionitril (8.6) 135,143, WAY200070 (pIC50 8.52 – 9.0) 133
Selective antagonists (pKi)	methyl-piperidino-pyrazole (8.57) 145	PHTPP 119, R,R-THC (8.44) 134,146

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>>aldosterone,deoxycortisone 139	corticosterone,cortisol,aldosterone,progesterone 139	progesterone
Endogenous agonists (pKi)	dihydrotestosterone (pKd 9.3) 147	–	aldosterone (Selective) (pIC50 9.8 – 10.0) 126,139	progesterone (Selective)
Selective agonists (pKi)	methyltrienolone (pEC50 < 5.0) 149, mibolerone (pIC50 8.96) 124	fluticasone, RU26988, RU28362	–	levonorgestrel 140, ORG2058
Selective antagonists (pKi)	hydroxyflutamide (pEC50 6.6) 149, PF0998425 (pIC50 7.1 – 7.5) 131, nilutamide (pIC50 7.07 – 7.12) 141	onapristone, ZK112993, mifepristone (pKd 9.4) 125,139	onapristone, RU28318, ZK112993, eplerenone (pIC50 1.0) 121,127	mifepristone, onapristone, ZK112993
Radioligands (Kd)	[3H]dihydrotestosterone (Agonist), [3H]mibolerone (Agonist), [3H]R1881 (Agonist)	[3H]dexamethasone (Agonist)	[3H]aldosterone (Agonist) (3x10-10 – 4x10-10 M - Rat) 123,144	[3H]ORG2058 (Agonist)