Ulcerative colitis

Disease ID:1054
Name:Ulcerative colitis
Associated with:3 targets
1 immuno-relevant target
21 immuno-relevant ligands
Synonyms
Inflammatory bowel disease 1; IBD1
Database Links
Disease Ontology: DOID:8577
OMIM: 266600
Orphanet: ORPHA771

Targets

TLR4
nucleotide binding oligomerization domain containing 2
heat shock protein family A (Hsp70) member 1 like
Comments:  Genetic mutations that cause amino acid changes in the HSPA1L protein have been identified in patients with UC.

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
mirikizumab
Immuno Disease Comments: Phase 2 clinical candidate for moderate to severe UC- see NCT02589665.
Clinical Use: Phase 2 clinical trials which will evaluate mirikizumab (as research code LY3074828) in Crohn's disease (NCT02891226), ulcerative colitis (NCT02589665) and plaque psoriasis (NCT02899988) patients are underway. | View clinical data
Bioactivity Comments: Mirikizumab (Antibody I) binds monkey IL-23 with a Kd of 0.056nM, and rabbit IL-23 with a Kd of 53nM, but does not bind rat or mouse IL-23 or human IL-12, IL-27 or IL-35 [2]. Antibody I blocks binding of IL-23 to the IL-23R in vitro, but does not inhibit IL-23 binding to IL-12Rβ1 (the other subunit of the functional IL-23R heterodimer). Effects of Antibody I in vivo are described in the associated patent documentation [2]. | View biological activity
mesalazine
Immuno Disease Comments: Approved drug for UC treatment and symptom prophylaxis.
Clinical Use: Mesalazine is used to treat active ulcerative colitis and to prevent symptom recurrence. It may also be used for the management of other types of inflammatory bowel disease (e.g. Crohn's disease). | View clinical data
olamkicept
Immuno Disease Comments: Phase 2 clinical candidate for active UC- see NCT03235752.
Clinical Use: A Phase 2 clinical trial evaluating olamkicept (using research code TJ301) in patients with active ulcerative colitis is registered with ClinicalTrials.gov but is not yet recruiting paticipants (as of December 2017-see NCT03235752). | View clinical data
prednisolone
Immuno Disease Comments: Glucocorticoid drug used to treat many inflammatory condtions including UC.
Clinical Use: This drug used as an antiinflammatory or immunosuppressive agent and is indicated for the treatment of various inflammatory pathologies, including acute asthma, suppression of inflammatory and allergic disorders, ulcerative colitis, Crohn's disease, idiopathic thrombocytopenic purpura, rheumatoid arthritis, polymyalgia rheumatica, systemic lupus erythematosus and chronic obstructive pulmonary disease (COPD). | View clinical data
ACTH
Immuno Disease Comments: A corticotropin used to treat the symptoms of many inflammatory disorders including UC
Clinical Use: Corticotropin is used to treat the symptoms of many allergic disorders, psoriasis and other skin conditions, eye conditions, arthritis, lupus, multiple sclerosis, ulcerative colitis and breathing disorders, for example. This peptide is also used to diagonse adrenocortical insufficiency. | View clinical data
Bioactivity Comments: Although we have recorded affinity data for ACTH at melanocortin receptors 1, 3, 4 and 5, affinity data for the human melanocortin receptor 2, the peptide's primary target, is lacking. As a peptide mimetic of ACTH we would expect corticotropin to have similar affinities to the endogenous peptide. | View biological activity
infliximab
Immuno Disease Comments: Approved monoclonal antibody therapy for UC.
Clinical Use: Used in the management of rheumatoid arthritis (in combination with ), ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease [29] and ulcerative colitis. | View clinical data
Bioactivity Comments: Infliximab has been reported to induce an anti-chimeric antibody response in almost 15% of Crohn's disease patients (47 tested) [23]. This indicates that as predicited, humans can mount an immune response to whole murine variable domains, and is the underlying rationale promoting the development of clinical antibodies with variable domains with more human character (i.e. humanised or fully human monoclonal developments). | View biological activity
golimumab
Immuno Disease Comments: An anti-TNFα therapy approved for CD.
Clinical Use: Used in adults with various inflammatory conditions [34] e.g. moderate to severe active rheumatoid arthritis [11], active psoriatic arthritis, active ankylosing spondylitis and moderate to severe ulcerative colitis. | View clinical data
corticotropin zinc hydroxide
Immuno Disease Comments: Historically used to treat UC, with use now discontinued.
Clinical Use: Historical clinical uses include the treatment of ulcerative colitis and other colonic disorders [22] and therapy of some collagen diseases [1]. | View clinical data
azathioprine
Immuno Disease Comments: Approved drug for UC.
Clinical Use: Used to reduce organ rejection in transplant patients and to treat autoimmune diseases such as rheumatoid arthritis, Crohn's disease, lupus erythematosus and ulcerative colitis. | View clinical data
Bioactivity Comments: Azathioprine is reported to inhibit peptidylarginine deiminase 4 (PADI4), albeit with very low in vitro affinity [12]. PADI enzymes catalyze the hydrolytic deimination of protein arginine to produce protein citrulline and ammonia [10] and cause chromatin decondensation. Dysregulated PADI4 activity may be involved in cancer progression as it is overexpressed in many malignant tumours, where enhanced chromatin decondensation is involved in promoting pluripotency and stem cell maintenance. | View biological activity
vedolizumab
Immuno Disease Comments: Approved therapeutic for UC.
Clinical Use: Approved to treat adult patients with moderate to severe ulcerative colitis or moderate to severe Crohn‘s disease. | View clinical data
Bioactivity Comments: In vitro, vedolizumab inhibits specific binding of α4β7 +ve lymphoma cells to immobilised MADCAM1 or fibronectin with IC50 values of 0.39nM and 0.14nM respectively [25]. Soler et al. (2009) also show by FACS analysis that vedolizumab binds specifically to cells exogenously expressing the α4 and β7 intergrin proteins [25]. | View biological activity
peficitinib
Immuno Disease Comments: Phase 2 trial NCT01959282 in UC has been completed.
Clinical Use: Peficitinib is being assessed in Phase III clinical trial as a potential treatment for rheumatoid arthritis (RA). A Phase IIa trial in patients with moderate to severe psoriasis has produced encouraging results [20]. | View clinical data
Bioactivity Comments: Note that some bioactivity data may be generated using peficitinib hydrobromide (PubChem CID 67998300). We have tagged JAK3 as the primary molecular target for this compound for data metric purposes only, and fully acknowledge its pan-JAK activity. | View biological activity
etrolizumab
Immuno Disease Comments: Phase 3 clinical candidate for UC.
Clinical Use: Etrolizumab is being evaluated in Phase III clinical trial as a potential treatment for Crohn's disease and ulcerative colitis [30]. | View clinical data
Bioactivity Comments: hu504.32R inhibits cell adhesion in assays performed as part of the patent application [7]; inhibiting α4β7-MAdCAM-1-mediated adhesion with an IC50 of 0.075nM, and αEβ7-E-cadherin-mediated adhesion with an IC50 of 3.96nM. | View biological activity
GLPG0974
Immuno Disease Comments: Phase 2 clinical candidate for UC; no active clinical trials.
Clinical Use: A Phase II clinical trial evaluating GLPG0974 in ulcerative colitis has been completed (NCT01829321). Safety, pharmacokinetics and pharmacodynamics of GLPG0974 in healthy subjects are reported in [16]. | View clinical data
Bioactivity Comments: GLPG0974 is reported to be selective for FFA2 [21] in a panel of 55 receptors, ion channels, and transporters tested in the Cerep ExpresSProfile selectivity set [3]. | View biological activity
ozanimod
Immuno Disease Comments: Phase 3 clinical candidate for UC (see NCT02531126).
Clinical Use: Ozanimod has reached Phase III clinical trial for its potential antiinflammatory effects in relapsing multiple sclerosis and ulcerative colitis. | View clinical data
Bioactivity Comments: Ozanimod is metabolized to , a compound which retains an activity profile indistinguishable from its parent [27]. | View biological activity
eldelumab
Immuno Disease Comments: No progress beyond Phase 2 trial.
Clinical Use: Eldelumab has been evaluated in Phase II clinical trials for rheumatoid arthritis [33] and ulcerative colitis (NCT00656890) [14]. The antibody showed efficacy in both conditions. | View clinical data
Bioactivity Comments: Eldelumab does not bind other identified CXCR3 ligands (a.k.a. MIG) and (a.k.a. ITAC) [6]. | View biological activity
mucosal addressin cell adhesion molecule 1
Immuno Disease Comments: A gut-specific ligand being investigated as a drug target for inflammatory bowel conditions.
Bioactivity Comments: MAdCAM-1 expression is elevated in intestinal biopsies from experimental models of colitis and from patients with Crohn's disease and ulcerative colitis. | View biological activity
deflazacort
Immuno Disease Comments: Approved corticosteroid that can be prescribed for UC.
Clinical Use: Deflazacort can be prescribed for many inflammatory conditions including asthma, rheumatoid arthritis, Crohn's disease, juvenile chronic arthritis, idiopathic thrombocytopenic purpura, polymyalgia rheumatica, systemic lupus erythematosus and ulcerative colitis. More recently approved to treat Duchenne muscular dystrophy [8]. | View clinical data
Bioactivity Comments: In vitro binding to rat kidney, thymus and liver glucocorticoid receptors is reported in [13]. | View biological activity
GSK2982772
Immuno Disease Comments: Clinical candidate in UC.
Clinical Use: GSK2982772 is in Phase 2 clinical trials in psoriasis (NCT02776033), rheumatoid arthritis (NCT02858492), and ulcerative colitis (NCT02903966). | View clinical data
Bioactivity Comments: In a screening panel 10μM GSK2982772 did not inhibit any of the 339 kinases tested by >50% (a level assessed as being inactive). GSK2982772 prevented TNF-induced necrotic cell death, and was effective in an ulcerative colitis explant assay for blocking spontaneous cytokine release [9]. | View biological activity
PF-06651600
Immuno Disease Comments: Phase 1 clinical candidate for UC (NCT02958865).
Clinical Use: PF-06651600 has completed Phase 1clinical trial for inflammatory bowel disease (see NCT02309827). Phase 1 studies in rheumatoid arthritis, ulcerative colitis and alopecia areata are underway. | View clinical data
Bioactivity Comments: PF-06651600 exhibits favourable selectivity against a screening panel of 305 kinases in vitro, and shows measurable inhibition of 7 of the 10 other kinases which share a cysteine residue analogous to Cys-909 in the JAK3 ATP binding site (these were BMX, ITK, TXK, TEC, BTK, BLK and HER4) [28].
ATP concentration for JAK3 is 4 μM at Km and for JAK1 is 40 μM at Km, but some assays reported in [28] were carried out at 1 mM ATP . | View biological activity
PF-00547659 31
Immuno Disease Comments: Phase 2 clinical candidate for UC (see NCT01771809).
Clinical Use: PF-00547659 has completed Phase 2 clinical trials for ulcerative colitis and Crohn's disease. Results from Phase 2 ulcerative colitis trial NCT01620255 were published by Vermeire et al. (2017) [31] | View clinical data
Bioactivity Comments: PF-00547659 binding exhbits >30-fold difference in target affinity between in vitro SPR (surface plasmon resonance) derived KD and clinically derived KD, thought to be due to conformational restrictions in membrane-bound MAdCAM-1 compared to soluble MAdCAM-1 [32]. | View biological activity
tofacitinib
Immuno Disease Comments: Approved by the FDA for the treatment of UC.
Clinical Use: Tofacitinib was intiailly approved for the treatment of rheumatoid arthritis. Marketed formulations contain tofacitinib citrate (PubChem CID 10174505).
In Feb 2016 Xelanj XR® was FDA approved as the first once-daily oral JAK inhibitor for rheumatoid arthritis.
In June 2018, FDA approval was expanded to include treatment of patients with moderate to severe ulcerative colitis (UC), subsequent to results from the Phase 3 OCTAVE studies, in which treatment of UC patients with tofacitinib met all primary endpoints and induced significant disase remission [15,19,24]. Xelanj XR® is not approved for UC.

A report in JCI Insight in September 2016 suggests that tofacitinib-induced immunosuppression can stimulate significant hair regrowth in patients with the autoimmune condition alopecia areata [5], although more extensive studies would need to be conducted before the drug could be approved for this indication. Click here to link to a list of tofacitinib/alopecia trials registered with ClinicalTrials.gov. | View clinical data
Bioactivity Comments: Like many first generation kinase inhibitors tofacitinib exhibits a high degree of broad kinome selectivity but is in reality a pan-JAK-inhibitor. Additional kinases inhibited by tofacitinib in biochemical and cellular assays are described in [17]. Tofacitinib is also reported to exhibit immunosuppressive activity which prevents organ rejection in mice and primates [4].
Despite clinical efficacy in ulcerative colitis, tofacitinib did not show significant efficacy as an induction and maintenance therapy over placebo, in Crohn's disease patients (as evaluated in Phase 2 studies NCT01393626 and NCT01393899) [18]. | View biological activity

References

Show »

1. BANGHART HE, WATANABE RK. (1956) Corticotropin-zinc hydroxide evaluation in the therapy of certain collagen diseases. Am Pract Dig Treat, 7 (12): 1957-62. [PMID:13372943]

2. Beidler CB, Bright SW, Girard DS, Kikly KK. (2015) Antibodies that bind to IL-23. Patent number: US9023358B2. Assignee: Eli Lilly and Co Ltd (GB). Priority date: 08/03/2013. Publication date: 05/05/2015.

3. Cerep. ExpresSProfile - P1. Accessed on 08/06/2015. Modified on 08/06/2015. http://www.cerep.fr, http://www.cerep.fr/cerep/users/pages/catalog/profiles/DetailProfile.asp?profile=2117

4. Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH et al.. (2003) Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science, 302 (5646): 875-8. [PMID:14593182]

5. Crispin MC, JKo JM, BCraiglow BG, Li S, Shankar G, JUrban JR, Chen JC, JCerise JE, Jabbari A, Winge MCG. (2016) Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight, 15 (1): e89776 Epub.

6. Deshpande S, Huang H, Srinivasan M, Cardarelli JM, Wang C, Passmore DB, Rangan V, Lane TE, Keirstead HS, Liu MT. (2012) IP-10 antibodies and their uses. Patent number: US8258266 B2. Assignee: Medarex, Inc.. Priority date: 10/12/2003. Publication date: 04/09/2012.

7. Fong S, Dennis MS. (2009) Humanized anti-beta7 antagonists and uses therefor. Patent number: US7528236 B2. Assignee: Genentech, Inc.. Priority date: 03/09/2004. Publication date: 09/05/2009.

8. Griggs RC, Miller JP, Greenberg CR, Fehlings DL, Pestronk A, Mendell JR, Moxley 3rd RT, King W, Kissel JT, Cwik V et al.. (2016) Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy. Neurology, 87 (20): 2123-2131. [PMID:27566742]

9. Harris PA, Berger SB, Jeong JU, Nagilla R, Bandyopadhyay D, Campobasso N, Capriotti CA, Cox JA, Dare L, Dong X et al.. (2017) Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases. J. Med. Chem., 60 (4): 1247-1261. [PMID:28151659]

10. Jones JE, Causey CP, Knuckley B, Slack-Noyes JL, Thompson PR. (2009) Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential. Curr Opin Drug Discov Devel, 12 (5): 616-27. [PMID:19736621]

11. Kay J, Matteson EL, Dasgupta B, Nash P, Durez P, Hall S, Hsia EC, Han J, Wagner C, Xu Z et al.. (2008) Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum., 58 (4): 964-75. [PMID:18383539]

12. Knuckley B, Luo Y, Thompson PR. (2008) Profiling Protein Arginine Deiminase 4 (PAD4): a novel screen to identify PAD4 inhibitors. Bioorg. Med. Chem., 16 (2): 739-45. [PMID:17964793]

13. Luzzani F, Glässer A. (1981) Differential binding in vitro to glucocorticoid receptors of deflazacort and prednisolone. Eur. J. Pharmacol., 76 (4): 427-30. [PMID:7327211]

14. Mayer L, Sandborn WJ, Stepanov Y, Geboes K, Hardi R, Yellin M, Tao X, Xu LA, Salter-Cid L, Gujrathi S et al.. (2014) Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study. Gut, 63 (3): 442-50. [PMID:23461895]

15. Motoya S, Watanabe M, Kim HJ, Kim YH, Han DS, Yuasa H, Tabira J, Isogawa N, Arai S, Kawaguchi I et al.. (2018) Tofacitinib induction and maintenance therapy in East Asian patients with active ulcerative colitis: subgroup analyses from three phase 3 multinational studies. Intest Res, 16 (2): 233-245. [PMID:29743836]

16. Namour F, Galien R, Van Kaem T, Van der Aa A, Vanhoutte F, Beetens J, Van't Klooster G. (2016) Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects. Br J Clin Pharmacol, 82 (1): 139-48. [PMID:26852904]

17. Ostrovskyi D, Rumpf T, Eib J, Lumbroso A, Slynko I, Klaeger S, Heinzlmeir S, Forster M, Gehringer M, Pfaffenrot E et al.. (2016) Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1). Future Med Chem, 8 (13): 1537-51. [PMID:27572962]

18. Panés J, Sandborn WJ, Schreiber S, Sands BE, Vermeire S, D'Haens G, Panaccione R, Higgins PDR, Colombel JF, Feagan BG et al.. (2017) Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials. Gut, 66 (6): 1049-1059. [PMID:28209624]

19. Panés J, Vermeire S, Lindsay JO, Sands BE, Su C, Friedman G, Zhang H, Yarlas A, Bayliss M, Maher S et al.. (2018) Tofacitinib in Patients with Ulcerative Colitis: Health-Related Quality of Life in Phase 3 Randomised Controlled Induction and Maintenance Studies. J Crohns Colitis, 12 (2): 145-156. [PMID:29028981]

20. Papp K, Pariser D, Catlin M, Wierz G, Ball G, Akinlade B, Zeiher B, Krueger JG. (2015) A phase 2a randomized, double-blind, placebo-controlled, sequential dose-escalation study to evaluate the efficacy and safety of ASP015K, a novel Janus kinase inhibitor, in patients with moderate-to-severe psoriasis. Br. J. Dermatol., 173 (3): 767-76. [PMID:25704750]

21. Pizzonero M, Dupont S, Babel M, Beaumont S, Bienvenu N, Blanqué R, Cherel L, Christophe T, Crescenzi B, De Lemos E et al.. (2014) Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic. J. Med. Chem., 57 (23): 10044-57. [PMID:25380412]

22. RIESE JA. (1957) The use of corticotropin-zinc hydroxide in the treatment of ulcerative colitis and other colonic disorders. Am. J. Gastroenterol., 28 (4): 452-9. [PMID:13469787]

23. Rutgeerts P, D'Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, Mayer L, Van Hogezand RA, Braakman T, DeWoody KL et al.. (1999) Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology, 117 (4): 761-9. [PMID:10500056]

24. Sandborn WJ, Su C, Sands BE, D'Haens GR, Vermeire S, Schreiber S, Danese S, Feagan BG, Reinisch W, Niezychowski W et al.. (2017) Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N. Engl. J. Med., 376 (18): 1723-1736. [PMID:28467869]

25. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. (2009) The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J. Pharmacol. Exp. Ther., 330 (3): 864-75. [PMID:19509315]

26. Takahashi S, Andreoletti G, Chen R, Munehira Y, Batra A, Afzal NA, Beattie RM, Bernstein JA, Ennis S, Snyder M. (2017) De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease. Genome Med, 9 (1): 8. [PMID:28126021]

27. Taylor Meadows KR, Steinberg MW, Clemons B, Stokes ME, Opiteck GJ, Peach R, Scott FL. (2018) Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus. PLoS ONE, 13 (4): e0193236. [PMID:29608575]

28. Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R et al.. (2017) Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans. J. Med. Chem., 60 (5): 1971-1993. [PMID:28139931]

29. van Dullemen HM, van Deventer SJ, Hommes DW, Bijl HA, Jansen J, Tytgat GN, Woody J. (1995) Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology, 109 (1): 129-35. [PMID:7797011]

30. Vermeire S, O'Byrne S, Keir M, Williams M, Lu TT, Mansfield JC, Lamb CA, Feagan BG, Panes J, Salas A et al.. (2014) Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet, 384 (9940): 309-18. [PMID:24814090]

31. Vermeire S, Sandborn WJ, Danese S, Hébuterne X, Salzberg BA, Klopocka M, Tarabar D, Vanasek T, Greguš M, Hellstern PA et al.. (2017) Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet, 390 (10090): 135-144. [PMID:28527704]

32. Wang M, Kussrow AK, Ocana MF, Chabot JR, Lepsy CS, Bornhop DJ, O'Hara DM. (2017) Physiologically relevant binding affinity quantification of monoclonal antibody PF-00547659 to mucosal addressin cell adhesion molecule for in vitro in vivo correlation. Br. J. Pharmacol., 174 (1): 70-81. [PMID:27760281]

33. Yellin M, Paliienko I, Balanescu A, Ter-Vartanian S, Tseluyko V, Xu LA, Tao X, Cardarelli PM, Leblanc H, Nichol G et al.. (2012) A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum., 64 (6): 1730-9. [PMID:22147649]

34. Zhou H, Jang H, Fleischmann RM, Bouman-Thio E, Xu Z, Marini JC, Pendley C, Jiao Q, Shankar G, Marciniak SJ et al.. (2007) Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis. J Clin Pharmacol, 47 (3): 383-96. [PMID:17322150]