phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta

Target id: 2155

Nomenclature: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta

Abbreviated Name: PI3Kδ

Family: Phosphatidylinositol-4,5-bisphosphate 3-kinase family, Phosphatidylinositol kinases

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF :     phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1044 1p36.2 PIK3CD phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta 44
Mouse - 1047 4 E2 Pik3cd phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta
Rat - 944 5q36 Pik3cd phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta
Previous and Unofficial Names
PI3Kdelta | p110δ/PIK3CD | phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta | phosphatidylinositol-4 | phosphatidylinositol 3-kinase catalytic delta polypeptide
Database Links
BRENDA
CATH/Gene3D
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3KBeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers
PDB Id:  4AJW
Resolution:  2.8Å
Species:  Mouse
References:  11
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of the murine class IA PI 3-kinase p110delta in complex with IC-87114.
PDB Id:  2X38
Ligand:  IC-87114
Resolution:  2.2Å
Species:  Mouse
References:  6
Enzyme Reaction
EC Number: 2.7.1.153

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
IPI549 Hs Inhibition 7.6 pKd 18
pKd 7.6 (Kd 2.3x10-8 M) [18]
PQR309 Hs Inhibition 7.6 pKd
pKd 7.6 (Kd 2.5x10-8 M)
LY 294002 Hs Inhibition 6.2 pKd 16
pKd 6.2 (Kd 7.1x10-7 M) [16]
taselisib Hs Inhibition 9.7 – 10.1 pKi 7,34
pKi 10.1 (Ki 7.9x10-11 M) [7]
pKi 9.7 (Ki 2.1x10-10 M) [34]
compound 82 [PMID: 21332118] Hs Inhibition 8.9 pKi 14
pKi 8.9 (Ki 1.2x10-9 M) [14]
pictilisib Hs Inhibition 8.8 pKi 7
pKi 8.8 (Ki 1.54x10-9 M) [7]
GDC-0077 Hs Inhibition 7.9 pKi 7
pKi 7.9 (Ki 1.22x10-8 M) [7]
IC-87114 Hs Inhibition ~7.7 pKi 29
pKi ~7.7 (Ki ~2x10-8 M) [29]
omipalisib Hs Inhibition 7.2 pKi 27
pKi 7.2 (Ki 6x10-8 M) [27]
KU-0060648 Hs Inhibition >10.0 pIC50 9
pIC50 >10.0 (IC50 <1x10-10 M) [9]
nemiralisib Hs Inhibition 9.9 pIC50 17
pIC50 9.9 (IC50 1.26x10-10 M) [17]
Description: In a homogeneous time-resolved fluorescence (HTRF) assay in the presence of 2mM ATP.
idelalisib Hs Inhibition 8.6 pIC50 30
pIC50 8.6 (IC50 2.5x10-9 M) in vitro activity against recombinant enzyme [30]
duvelisib Hs Inhibition 8.6 pIC50 45
pIC50 8.6 (IC50 2.5x10-9 M) [45]
pictilisib Hs Inhibition 8.5 pIC50 19
pIC50 8.5 (IC50 3x10-9 M) [19]
PI-103 Hs Inhibition 8.5 pIC50 39
pIC50 8.5 (IC50 3x10-9 M) [39]
ZSTK474 Hs Inhibition 8.2 – 8.3 pIC50 47-48
pIC50 8.2 – 8.3 (IC50 6x10-9 – 5x10-9 M) [47-48]
torin 2 Hs Inhibition 8.3 pIC50 31
pIC50 8.3 (IC50 5.67x10-9 M) [31]
AZD8835 Hs Inhibition 8.2 pIC50 5
pIC50 8.2 (IC50 5.7x10-9 M) [5]
apitolisib Hs Inhibition 8.2 pIC50 42
pIC50 8.2 (IC50 6.7x10-9 M) [42]
dactolisib Hs Inhibition 8.1 pIC50 33
pIC50 8.1 (IC50 7x10-9 M) [33]
AZD8186 Hs Inhibition 7.9 pIC50 22
pIC50 7.9 (IC50 1.2x10-8 M) [22]
RP5264 Hs Inhibition 7.9 pIC50 43
pIC50 7.9 (IC50 1.383x10-8 M) [43]
PI-3065 Hs Inhibition 7.8 pIC50 2
pIC50 7.8 (IC50 1.5x10-8 M) [2]
AMG319 Hs Inhibition 7.7 pIC50 13
pIC50 7.7 (IC50 1.8x10-8 M) [13]
leniolisib Hs Inhibition 7.6 pIC50 12
pIC50 7.6 (IC50 2.3x10-8 M) [12]
Description: In vitro enzyme assay
pilaralisib Hs Inhibition 7.4 pIC50 47
pIC50 7.4 (IC50 3.6x10-8 M) [47]
LY3023414 Hs Inhibition 7.4 pIC50 4
pIC50 7.4 (IC50 3.8x10-8 M) [4]
CUDC-907 Hs Inhibition 7.4 pIC50 38
pIC50 7.4 (IC50 3.9x10-8 M) [38]
VS-5584 Hs Inhibition 7.4 pIC50 24
pIC50 7.4 (IC50 4.2x10-8 M) [24]
AZD6482 Hs Inhibition 7.1 pIC50 35
pIC50 7.1 (IC50 8x10-8 M) [35]
TGX-221 Hs Inhibition 7.0 pIC50 26
pIC50 7.0 (IC50 1x10-7 M) [26]
PP121 Hs Inhibition 6.8 pIC50 3
pIC50 6.8 (IC50 1.5x10-7 M) [3]
LY 294002 Hs Inhibition 6.7 pIC50 9
pIC50 6.7 (IC50 2.2x10-7 M) [9]
INK-128 Hs Inhibition 6.6 pIC50 25
pIC50 6.6 (IC50 2.3x10-7 M) [25]
TG-100-115 Hs Inhibition 6.6 pIC50 37
pIC50 6.6 (IC50 2.35x10-7 M) [37]
alpelisib Hs Inhibition 6.5 pIC50 21
pIC50 6.5 (IC50 2.9x10-7 M) [21]
PI 3-Kg inhibitor Hs Inhibition 6.5 pIC50 8
pIC50 6.5 (IC50 3x10-7 M) [8]
compound 28 [PMID: 24387221] Hs Inhibition 6.3 pIC50 10
pIC50 6.3 (IC50 4.68x10-7 M) [10]
CH5132799 Hs Inhibition 6.3 pIC50 36
pIC50 6.3 (IC50 5x10-7 M) [36]
IC-87114 Hs Inhibition 6.3 pIC50 41
pIC50 6.3 (IC50 5x10-7 M) [41]
PIK-75 Hs Inhibition 6.3 pIC50 28
pIC50 6.3 (IC50 5.1x10-7 M) [28]
eCF309 Hs Inhibition 5.7 pIC50 20
pIC50 5.7 (IC50 1.84x10-6 M) [20]
Description: In a biochemical assay.
serabelisib Hs Inhibition >5.0 pIC50 40
pIC50 >5.0 (IC50 <1x10-5 M) [40]
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
PIK-108 Hs Negative 6.2 pIC50 11
pIC50 6.2 (IC50 6.58x10-7 M) [11]
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 15,46

Key to terms and symbols Click column headers to sort
Target used in screen: PIK3CD
Ligand Sp. Type Action Affinity Units
pictilisib Hs Inhibitor Inhibition 8.3 pKd
PI-103 Hs Inhibitor Inhibition 7.8 pKd
PP-242 Hs Inhibitor Inhibition 7.5 pKd
TG-100-115 Hs Inhibitor Inhibition 6.6 pKd
ruboxistaurin Hs Inhibitor Inhibition <5.5 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
erlotinib Hs Inhibitor Inhibition <5.5 pKd
GSK690693 Hs Inhibitor Inhibition <5.5 pKd
masitinib Hs Inhibitor Inhibition <5.5 pKd
A-674563 Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
The potential for PI3kδ as ta arget in immuno-oncology is discussed in [1]
PI3Kδ is preferentially expressed in cells of hemopoietic lineage and is involved in neutrophil chemotaxis. It is the only PI3K isoform with expression restricted to leukocytes. Genetic and pharmacological inactivation of PI3Kδ indicates its importantance for the function of T cells, B cell, mast cells and neutrophils. PI3kδ is a promising target for drugs for preventing or treating inflammation, autoimmunity and transplant rejection [23] with selective PI3Kδ inhibitors of particular relevance- see for example AMG319 [13] and leniolisib [12].
Immuno Cell Type Associations
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
Comment: 
References:  44
Immuno Cell Type:  T cells
Cell Ontology Term:   alpha-beta T cell (CL:0000789)
Comment: 
References:  44
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process ID:  2
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  mast cell chemotaxis (GO:0002551) TAS
inflammatory response (GO:0006954) TAS
T cell chemotaxis (GO:0010818) TAS
neutrophil chemotaxis (GO:0030593) TAS
natural killer cell chemotaxis (GO:0035747) TAS
B cell chemotaxis (GO:0035754) TAS
mast cell degranulation (GO:0043303) TAS
innate immune response (GO:0045087) TAS
neutrophil extravasation (GO:0072672) TAS
References: 
Immuno Process:  T cell (activation)
Immuno Process ID:  4
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  adaptive immune response (GO:0002250) TAS
T cell differentiation (GO:0030217) TAS
T cell activation (GO:0042110) TAS
References: 
Immuno Process:  B cell (activation)
Immuno Process ID:  5
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  adaptive immune response (GO:0002250) TAS
B cell activation (GO:0042113) TAS
References: 
Immuno Process:  Immune regulation
Immuno Process ID:  6
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  positive regulation of neutrophil apoptotic process (GO:0033031) IMP
T cell receptor signaling pathway (GO:0050852) TAS
B cell receptor signaling pathway (GO:0050853) TAS
References: 
Immuno Process:  Immune system development
Immuno Process ID:  8
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  natural killer cell differentiation (GO:0001779) TAS
T cell differentiation (GO:0030217) TAS
mast cell differentiation (GO:0060374) TAS
References: 
Immuno Process:  Cytokine production & signalling
Immuno Process ID:  9
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  cytokine production (GO:0001816) TAS
References: 
Immuno Process:  Chemotaxis & migration
Immuno Process ID:  10
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  mast cell chemotaxis (GO:0002551) TAS
T cell chemotaxis (GO:0010818) TAS
neutrophil chemotaxis (GO:0030593) TAS
natural killer cell chemotaxis (GO:0035747) TAS
B cell chemotaxis (GO:0035754) TAS
neutrophil extravasation (GO:0072672) TAS
References: 
Immuno Process:  Cellular signalling
Immuno Process ID:  11
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  natural killer cell differentiation (GO:0001779) TAS
natural killer cell activation (GO:0030101) TAS
T cell differentiation (GO:0030217) TAS
T cell activation (GO:0042110) TAS
B cell activation (GO:0042113) TAS
mast cell degranulation (GO:0043303) TAS
T cell receptor signaling pathway (GO:0050852) TAS
B cell receptor signaling pathway (GO:0050853) TAS
References: 
Tissue Distribution
Leukocytes
Species:  Human
Technique:  Northern blot
References:  44
Lymphoid and myeloid cell populations, T cells, B cells (N.B. platelets negative)
Species:  Human
Technique:  Immunocytochemistry
References:  44
Spleen and thymus
Species:  Rat
Technique:  Immunohistochemistry
References:  44
Clinically-Relevant Mutations and Pathophysiology
Disease:  Activated PI3K delta syndrome
Description: A rare autosomal dominant, genetic disease causing primary immunodeficiency and characterised by lymphadenopathy, immunodeficiency leading to recurrent infections, and an increased risk of EBV-associated lymphoma.
Synonyms: APDS/PASLI
Immunodeficiency 14
p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency
OMIM: 615513
Orphanet: ORPHA397596
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense, gain of function Human N334K; E525K; E1021K 1002 C>A; 1573 G>A; 3061 G>A N334K is in the C2 domain, E525K is in the helical domain and E1021K is in the C-lobe of the kinase domain. 32
General Comments
PI3Kδ belongs to the class IA phospho-inositide-3-kinases (PI3Ks). In common with PI3Kα and PI3Kβ, PI3Kδ displays a broad phosphoinositide lipid substrate specificity. It interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras. Expression of PI3Kδ is restricted to leukocytes [44], whereas PI3Kα and PI3Kβ are widely expressed.

References

Show »

1. Adams JL, Smothers J, Srinivasan R, Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov14 (9): 603-22. [PMID:26228631]

2. Ali K, Soond DR, Piñeiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H et al.. (2014) Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature510 (7505): 407-11. [PMID:24919154]

3. Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM, Knight ZA. (2008) Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat. Chem. Biol.4 (11): 691-9. [PMID:18849971]

4. Barda DA, Mader MM. (2013) PI3 kinase/mTOR dual inhibitor. Patent number: US8440829 B2. Assignee: Eli Lilly And Company. Priority date: 14/01/2011. Publication date: 14/05/2013.

5. Barlaam B, Cosulich S, Delouvrié B, Ellston R, Fitzek M, Germain H, Green S, Hancox U, Harris CS, Hudson K et al.. (2015) Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers. Bioorg. Med. Chem. Lett.25 (22): 5155-62. [PMID:26475521]

6. Berndt A, Miller S, Williams O, Le DD, Houseman BT, Pacold JI, Gorrec F, Hon WC, Liu Y, Rommel C et al.. (2010) The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat. Chem. Biol.6 (2): 117-24. [PMID:20081827]

7. Braun M-G, Hanan E, Staben ST, Heald RA, Macleod C, Elliott R. (2017) Benzoxazepin oxazolidinone compounds and methods of use. Patent number: US20170015678. Assignee: Genentech, Inc.. Priority date: 02/07/2015. Publication date: 19/01/2017.

8. Camps M, Rückle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Françon B et al.. (2005) Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat. Med.11 (9): 936-43. [PMID:16127437]

9. Cano C, Saravanan K, Bailey C, Bardos J, Curtin NJ, Frigerio M, Golding BT, Hardcastle IR, Hummersone MG, Menear KA et al.. (2013) 1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity. J. Med. Chem.56 (16): 6386-401. [PMID:23855836]

10. Certal V, Carry JC, Halley F, Virone-Oddos A, Thompson F, Filoche-Rommé B, El-Ahmad Y, Karlsson A, Charrier V, Delorme C et al.. (2014) Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers. J. Med. Chem.57 (3): 903-20. [PMID:24387221]

11. Certal V, Halley F, Virone-Oddos A, Delorme C, Karlsson A, Rak A, Thompson F, Filoche-Rommé B, El-Ahmad Y, Carry JC et al.. (2012) Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. J. Med. Chem.55 (10): 4788-805. [PMID:22524426]

12. Cooke NG, Fernandes GDSP, Graveleau N, Hebach C, Hogenauer K, Hollingworth G, Smith AB, Soldermann N, Stowasser F, Strang R et al.. (2012) Tetrahydro-pyrido-pyrimidine derivatives. Patent number: WO2012004299. Assignee: Novartis Ag. Priority date: 06/07/2010. Publication date: 12/01/2012.

13. Cushing TD, Hao X, Shin Y, Andrews K, Brown M, Cardozo M, Chen Y, Duquette J, Fisher B, Gonzalez-Lopez de Turiso F et al.. (2015) Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease. J. Med. Chem.58 (1): 480-511. [PMID:25469863]

14. D'Angelo ND, Kim TS, Andrews K, Booker SK, Caenepeel S, Chen K, D'Amico D, Freeman D, Jiang J, Liu L et al.. (2011) Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors. J. Med. Chem.54 (6): 1789-811. [PMID:21332118]

15. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol.29 (11): 1046-51. [PMID:22037378]

16. Dittmann A, Werner T, Chung CW, Savitski MM, Fälth Savitski M, Grandi P, Hopf C, Lindon M, Neubauer G, Prinjha RK et al.. (2014) The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains. ACS Chem. Biol.9 (2): 495-502. [PMID:24533473]

17. Down K, Amour A, Baldwin IR, Cooper AW, Deakin AM, Felton LM, Guntrip SB, Hardy C, Harrison ZA, Jones KL et al.. (2015) Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease. J. Med. Chem.58 (18): 7381-99. [PMID:26301626]

18. Evans CA, Liu T, Lescarbeau A, Nair SJ, Grenier L, Pradeilles JA, Glenadel Q, Tibbitts T, Rowley AM, DiNitto JP et al.. (2016) Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate. ACS Med Chem Lett7 (9): 862-7. [PMID:27660692]

19. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA et al.. (2008) The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . J. Med. Chem.51 (18): 5522-32. [PMID:18754654]

20. Fraser C, Carragher NO, Unciti-Broceta A. (2016) eCF309: a potent, selective and cell-permeable mTOR inhibitor. Med. Chem. Commun.7 (3): 471-477.

21. Furet P, Guagnano V, Fairhurst RA, Imbach-Weese P, Bruce I, Knapp M, Fritsch C, Blasco F, Blanz J, Aichholz R et al.. (2013) Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett.23 (13): 3741-8. [PMID:23726034]

22. Hancox U, Cosulich S, Hanson L, Trigwell C, Lenaghan C, Ellston R, Dry H, Crafter C, Barlaam B, Fitzek M et al.. (2015) Inhibition of PI3Kβ signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel. Mol. Cancer Ther.14 (1): 48-58. [PMID:25398829]

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25. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, Shi EY, Stumpf CR, Christensen C, Bonham MJ et al.. (2012) The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature485 (7396): 55-61. [PMID:22367541]

26. Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y et al.. (2005) PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat. Med.11 (5): 507-14. [PMID:15834429]

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Phosphatidylinositol kinases: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta. Last modified on 15/08/2017. Accessed on 23/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2155.