Featured New Products 2010

Highlighted products added to the Tocris Bioscience range during 2010

December 2010

mGlu₂ antagonist

2913 | Ro 64-5229

IC₅₀ = 0.11 μM. Selective and non-competitive. Inhibits GTPγ³⁵S binding to mGlu₂-containing membranes.

K_i values are 0.29 μM and 1.11 μM for Bcl-2 and Bcl-XL respectively. Inhibits the angiogenic potential of endothelial cells in vitro. Induces S-phase arrest and apoptosis in pancreatic cancer cell lines; also inhibits the activation of Notch-1 and Jagged-1 in vitro and in vivo.

Selective NOP receptor antagonist

3573 | SB 612111

K_i values are 0.33, 57.6, 160.5 and 2109 nM for NOP, μ-, κ- and δ-receptors respectively. Antagonizes the pronociceptive action of nociceptin (Cat. No. 0910) in an acute pain model. Potentiates the action of morphine in morphine-tolerant animals and blocks hyperalgesia in an inflammatory pain model.

Modulator of voltage-sensitive Ca²⁺ channels

3775 | Pregabalin

Anticonvulsant and antiepileptic; also used to treat neuropathic pain. Binds with high affinity and selectivity to the α₂δ subunit of voltage-sensitive Ca²⁺ channels and modulates their activity. Displays anxiolytic-like activity in ethological and conflict models of anxiety. Analog of GABA (Cat. No. 0344).

VLA-4 antagonist

3900 | TCS 2314

Integrin very late antigen-4 (VLA-4; α₄β₁) antagonist (IC₅₀ = 4.4 nM). Blocks the activation of inflammatory cells.

November 2010

TRPM8 blocker

3989 | AMTB

TRPM8 channel blocker. Inhibits icilin-induced (Cat. No. 1531) TRPM8 channel activation in a rat model (pIC₅₀ = 6.23).

H₃ receptor inverse agonist/antagonist

3743 | BF 2649

Histamine H₃ receptor inverse agonist (EC₅₀ = 1.5 nM) and antagonist (K_i = 0.16 nM). Exhibits nootropic effects in cognitive disorders; reduces locomotor hyperactivity induced by methamphetamine. Brain penetrant.

High affinity CB₁ antagonist

3921 | NIDA 41020

High affinity CB₁ receptor antagonist (K_i = 4.1 nM). Exhibits significantly reduced lipophilicity compared to other CB₁ antagonists.

Inhibitor of P-gp-mediated MDR

4042 | PSC 833

P-glycoprotein (P-gp) modulator; inhibits P-gp-mediated multidrug-resistance (MDR). Reverses resistance to several cytotoxic drugs including mitoxantrone and doxorubicin (resistance factors are 2.0 and 6.5 respectively) in human MDR cancer cell lines. Non-immunosuppressive analogue of cyclosporin A (Cat. No. 1101).

October 2010

Positive allosteric modulator of hCaSR

3815 | R 568

Allosteric agonist of the human calcium-sensing receptor (hCaSR). Exhibits calcimimetic activity. Has the ability to restore function to hCaSR mutants that cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). Exerts a suppressive effect on parathyroid (PT) hormone secretion; inhibits PT cell proliferation in rats with renal insufficiency.

Potent GSK-3β inhibitor

3869 | TCS 2002

IC₅₀ = 35 nM. Oral adminstration inhibits cold water stress-induced tau hyperphosphorylation in the mouse brain.

Potent, selective and reversible CerK inhibitor

3960 | NVP 231

IC₅₀ = 12 nM in vitro. Displays selectivity for ceramide kinase (CerK) over sphingosine kinases (IC₅₀ ≥100 μM) and other lipid kinases.

Selective H₄ receptor antagonist

4021 | JNJ 7777120

Displays high affinity (K_i = 4.5 nM) and is >1000-fold selective for H₄ over other histamine receptors.

S6K1 inhibitor

4032 | PF 4708671

Cell-permeable inhibitor of p70 ribosomal S6 kinase (S6K1 isoform) (K_i = 20 nM; IC₅₀ = 160 nM). Suppresses the S6K1-mediated phosphorylation of S6, Rictor and mTOR in response to IGF1; displays no effect on the activity of RSK and MSK in vivo. Exhibits no significant inhibition of S6K2 or other AGC kinases (e.g. Akt, PKA and ROCK) in vitro.

September 2010

Dynamin inhibitor

3982 | Mdivi 1

IC₅₀ = 1 - 10 μM. Attenuates Dnm1- and Drp1-mediated mitochondrial division. Inhibits mitochondrial outer membrane permeabilization (MOMP) and attenuates apoptosis.

Hsp70 inhibitor

3803 | VER 155008

IC₅₀ = 0.5 μM. Inhibits cell proliferation of multiple human tumor cell lines in vitro. Also binds Hsc70 and Grp78; selective against Hsp90β.

Positive allosteric modulator of mGlu₂

3949 | CBiPES

IC₅₀ = 98.2 nM. Mimics the action of LY 379268 (Cat. No. 2453); attenuates ketamine-evoked histamine release in vivo.

Potent γ-secretase inhibitor

2870 | BMS 299897

IC₅₀ = 12 nM. Inhibits Aβ40 and Aβ42 formation in vitro (IC₅₀ values are 7.4 and 7.9 nM respectively) and reduces Aβ in the brain, plasma and cerebrospinal fluid in vivo. Exhibits no Notch toxicity. Brain penetrant.

α5-selective GABA_A inverse agonist

3817 | MRK 016

EC₅₀ = 3 nM. Exhibits affinity at benzodiazepine binding site of recombinant human GABA_A receptors (K_i values are 0.77 nM, 0.83 nM, 0.85 nM and 1.4 nM for α3-, α1-, α2-, and α5-containing respectively). Increases long-term potentiation (LTP) in mouse hippocampal slices. Exhibits no anxiogenic or proconvulsant activity.

August 2010

Selective inhibitor of TGF-βRI

3742 | SJN 2511

IC₅₀ values are 0.004 and 0.023 μM for ALK5 autophosphorylation and ALK5 binding respectively. Selective for ALK5 over a range of kinases, including p38 MAPK, JNK1 and GSK3 (IC₅₀ > 16 μM). Enhances the efficiency of cellular reprogramming.

Subtype-selective GABA_A receptor agonist

3941 | TCS 1205

In vitro K_i values are 14 and 121 nM for GABA_A α2 and GABA_A α1 respectively. Exhibits non-sedative anxiolytic activity in vivo.

D₃ antagonist and D₂ partial agonist

3940 | GSK 789472

pEC₅₀ values are < 5.5 and 8.3 respectively. Selective against the D₄ receptor in both agonist and antagonist assays. Brain penetrant.

Potent and selective MCH₁ antagonist

3359 | ATC 0065

IC₅₀ = 15.7 nM. Displays > 96-fold selectivity over MCH₂. Exhibits antidepressant and anxiolytic activity in vivo. Also displays affinity for 5-HT_1A and 5-HT_2B receptors (IC₅₀ values are 62.9 and 266 nM respectively). Orally active.

Selective GSK-3 inhibitor

3966 | AR-A 014418

IC₅₀ = 104 nM. Exhibits specificity for GSK-3 over cdk2 and cdk5 (IC₅₀ values are > 100 μM) and over 26 other kinases. Inhibits β-amyloid-mediated neurodegeneration in hippocampal slices.

July 2010

Axin stabilizer

3532 | endo-IWR 1

Inhibitor of Wnt signaling. Induces an increase in Axin2 protein levels; promotes β-catenin phosphorylation by stabilizing Axin-scaffolded destruction complexes.

High affinity 5-HT_1A receptor antagonist

3282 | NAD 299

K_i = 0.6 nM in vitro. Enhances the action of selective 5-HT reuptake inhibitors and reverses citalopram-induced inhibition of serotonergic cell firing.

GSK-3β inhibitor

3835 | TWS 119

IC₅₀ = 30 nM. Induces neuronal differentiation in pluripotent murine embryonal carcinoma cells and embryonic stem cells (ESCs).

TRPV1 antagonist

3875 | BCTC

Inhibits acid- and capsaicin-induced activation of rat TRPV1 receptors (IC₅₀ values are 6.0 and 35 nM respectively). Displays analgesic properties in rat models of inflammatory and neuropathic pain. CNS penetrant.

June 2010

Selective nNOS inhibitor

3319 | ARL 17477

IC₅₀ values are 1 and 17 μM for neuronal NOS and endothelial NOS respectively. Reduces ischemic cell damage after middle cerebral artery (MCA) occlusion in rats. Displays a synergistic neuroprotective effect when combined with either an NMDA or AMPA receptor antagonist.

Positive allosteric modulator of M₄ receptors

3383 | VU 152100

EC₅₀ = 380 nM. Induces 21-fold shift in ACh potency at M₄ receptor. Displays no activity at other mAChR subtypes.

Selective S1P₁ receptor agonist

3601 | CYM 5442

EC₅₀ = 1.35 nM. Activates S1P₁-mediated p42/p44 MAPK phosphorylation in CHO-K1 cells transfected with S1P₁. Induces acute lymphopenia in mice. Brain penetrant.

Orally active p38α and p38β inhibitor

3916 | VX 702

K_D values are 3.7 and 17 nM respectively.

Wnt production inhibitor

3533 | IWP 2

Inactivates Porcn, a membrane-bound O-acyltransferase (MBOAT), and selectively inhibits palmitoylation of Wnt. Blocks Wnt-dependent phosphorylation of Lrp6 receptor and Dvl2, and β-catenin accumulation.

May 2010

Potent and selective H₄ receptor antagonist

3640 | A 987306

pK_i values are 8.24 and 8.47 in human and rat H₄ receptors respectively. Displays 162-fold, 620-fold, and > 1600-fold selectivity over human H₃, H₁ and H₂ receptors. Blocks zymosan-induced neutrophil reflux and attenuates thermal hypersensitivity in vivo (ED₅₀ = 42 μmol/kg, ip).

Potent P2X₄ receptor antagonist

3579 | 5-BDBD

Blocks P2X₄-mediated currents in Chinese hamster ovary cells (IC₅₀ = 0.50 μM).

Potent and selective I_Ks blocker

3899 | JNJ 303

IC₅₀ = 64 nM. Displays no effects on other cardiac channels; IC₅₀ values are 3.3, >10, 11.1 and 12.6 μM for I_Na, I_Ca, I_to and I_Kr channels respectively. Prolongs QT and causes unprovoked torsades de pointes (TdP).

Potent NPY Y₅ antagonist

3562 | LU AA33810

K_i = 1.5 nM in vitro. Displays ≥ 3300-fold affinity for Y₅ over Y₁, Y₂ and Y₄ receptors. Also binds human 5-HT_2B and 5-HT_1A receptors (K_i values are 247 and 478 nM respectively). Exerts anxiolytic- and antidepressant-like effects in rat models of stress sensitivity.

Potent, dual orexin receptor antagonist

3818 | TCS 1102

K_i values are 0.2 and 3 nM for OX₂ and OX₁ receptors respectively. Inhibits ADL-orexin B-mediated locomotion following i.p. administration in vivo. Brain penetrant.

April 2010

Potent and selective PI 3-kinase γ (PI3Kγ) inhibitor

3578 | AS 605240

Displays 30-fold selectivity over PI3Kδ and PI3Kβ and 7.5-fold selectivity over PI3Kα. Suppresses the progression of joint inflammation and damage in both lymphocyte-independent and lymphocyte-dependent mouse models of rheumatoid arthritis.

Potent and selective NPY Y₅ antagonist

3677 | NPY 5RA972

IC₅₀ values are 3.1, >10000, >10000 and >10000 nM for Y₅, Y₁, Y₂ and Y₄ receptors respectively. Does not block NPY-induced feeding in vivo. Orally active and brain penetrant.

Potent and selective ERβ agonist

3523 | FERb 033

K_i = 7.1 nM, EC₅₀ = 4.8 nM. Displays 62-fold selectivity over ERα.

Potent and selective NOP antagonist

3661 | BAN ORL 24

IC₅₀ values are 0.27, 2500, 6700 and > 10000 nM for NOP, κ-, μ- and δ-receptors respectively. Inhibits nociceptin-induced stimulation of [³⁵S]-GTPγS binding and Ca²⁺ mobilization in CHO cells in vitro.

Potent and selective H₄ antagonist

3753 | A 943931

pK_i values are 7.15 and 8.12 at human and rat receptors respectively. Blocks inflammation in a peritonitis mouse model and displays efficacy in inflammatory pain and neuropathic pain models.

March 2010

Subtype-selective α4β2 partial agonist

3754 | Varenicline

K_i values are 0.06, 240, 322 and 3540 nM for α4β2, α3β4, α7, α1βγδ receptors respectively. Reduces nicotine-evoked dopamine release in vitro and decreases nicotine self-administration in vivo.

Potent VEGFR, PDGFRβ and KIT inhibitor

3768 | Sunitinib

K_i values are 2, 9, 17, 8 and 4 nM for VEGFR -1, -2, -3, PDGFRβ and KIT respectively. Also inhibits cellular receptor phosphorylation of FLT3, RET and CSF-1R. Exhibits antiangiogenic and antitumor activity in multiple xenograft models.

Potent, selective CB₂ agonist

3556 | SER 601

K_i values are 6.3 nM and 1.2 μM for CB₂ and CB₁ receptors respectively. Displays analgesic activity in the formalin test in mice.

Potent and selective P2Y₁₂ antagonist

3321 | AR-C 66096

Blocks ADP-induced inhibition of adenylyl cyclase in vitro (PK_B =7.6) and inhibits ADP-induced aggregation of washed human platelets (pIC₅₀ = 8.16).

Dual CK1/cdk inhibitor

3610 | (R)-DRF053

IC₅₀ values are 220, 80 and 14 nM for cdk1/cyclin B, cdk5/p25 and CK1 respectively. Selective over GSK-3 α/β (IC₅₀= 4.1 μM). Also shown to inhibit amyloid-β production in N2A-APP₆₉₅ cells.

February 2010

High affinity and selective GPR30 antagonist

3678 | G-15

K_i = 20 nM. Displays no affinity for ERα and ERβ at concentrations up to 10 μM. Inhibits agonist-induced calcium mobilization in vitro (EC₅₀ of ~185 nM) and antagonizes the antidepressive effects of estrogen in vivo.

Selective Pim kinase inhibitor

3714 | TCS PIM-1 4a

IC₅₀ values are 24 and 100 nM for Pim-1 and Pim-2 respectively. Displays selectivity over a panel of ~50 other kinases tested. Exhibits cytotoxicity in PC3 prostate carcinoma cells in vitro (IC₅₀ = 17 μM).

Selective mTOR inhibitor

3725 | KU 0063794

IC₅₀ ~10 nM for mTORC1 and mTORC2 respectively. Displays no activity at PI 3-K or 76 other kinases tested. Suppresses cell growth and induces G₁ cell cycle arrest in vitro.

Primes ESCs for differentiation

3741 | Stauprimide

Interacts with NME2 and inhibits its nuclear translocation. Increases the efficiency of directed differentiation of mouse and human embryonic stem cells (ESCs) in vitro.

Potent, collagenase-selective MMP inhibitor

2916 | Ro 32-3555

K_i values are 3.0, 3.4, 4.4, 59, 154 and 527 nM for MMP-1, MMP-13, MMP-8, MMP-9, MMP-2 and MMP-3 respectively. Inhibits cartilage breakdown in vitro and in vivo and displays antiarthritic activity. Orally active.

January 2010

PAM of δ-containing GABA_A receptors

3679 | DS2

EC₅₀ = 142 nM for α4β3δ receptors. Displays no effects on GABA responses mediated by α4β3γ2 and α1β3γ2 receptors.

Potent and selective P2X₇ antagonist

3701 | A 740003

IC₅₀ values are 18 and 40 nM for rat and human receptors respectively. Displays selectivity over a variety of P2X and P2Y receptors up to a concentration of 100 μM. Reduces nociception in animal models of persistent neuropathic and inflammatory pain.

Potent and selective CCR3 antagonist

3650 | SB 328437

IC₅₀ = 4 nM. Displays > 2500-fold selectivity over C5aR, LTD₄, CCR7, CXCR1 and CXCR2 receptors. Inhibits eotaxin-, eotaxin-2- and MCP-4-induced Ca²⁺ mobilization.

Tankyrase inhibitor; inhibits wnt signaling

3748 | XAV 939

IC₅₀ values are 0.011 and 0.004 μM for TNKS1 and TNKS2 respectively. Antagonizes wnt signaling via stimulation of β-catenin degradation and stabilization of axin.

Selective TRPV4 ligands

3745 | RN 1747 & 3746 | RN 1734

RN 1747 is a selective TRPV4 agonist (EC₅₀ values are 0.77, 4.0 and 4.1 μM for hTRPV4, mTRPV4 and rTRPV4 respectively) that also antagonizes TRPM8 at relevant concentrations (IC₅₀ = 4 μM). RN 1734 is a selective TRPV4 antagonist (IC₅₀ values are 2.3, 5.9 and 3.2 μM for hTRPV4, mTRPV4 and rTRPV4 receptors respectively).