NPY2R Antagonist
BIIE0246
Since its introduction in 1999, BIIE0246 became the gold standard as pharmacological tool for the in vitro and in vivo study of Y2 receptor mediated effects. Its use has been documented in over 100+ scientific publications. It is offered together with its negative control, BIIE0212, a congeneric analogue with 400-fold lower affinity towards the Y2 receptor than BIIE0246.
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The neuropeptide Y Y2 receptor (Y2R) is a member of the neuropeptide Y (NPY) receptor family which in humans consists of the four rhodopsin-like (class A) GPCRs: Y1, Y2, Y4, and Y5.
NPY receptors are activated by a family of structurally related tyrosine-rich polypeptides, namely NPY, PYY (peptide tyrosine-tyrosine) and PP (pancreatic polypeptide) having a common length of 36 amino acids and an amidated C-terminus.
Y2 receptors are expressed in both the peripheral and central nervous system where they predominantly are located on presynaptic neurons. Brain regions with high expression levels of Y2 receptors are hippocampus, thalamus, hypothalamus and amygdala.
Y2 receptors are involved in the modulation of various (patho-) physiological processes including memory retention, anxiety, arousal, alcohol consumption and energy homeostasis. In particular, the appetite suppressant effect elicited by the activation of Y2 receptors expressed in the arcuate nucleus of the hypothalamus attracted considerable attention.
Recently, Beck-Sickinger et al. proposed a structural model for the binding mode of BIIE0246 in the Y2R binding site based on mutagenesis data and computational docking2.
3D structure of BIIE0246, a non-peptide NPY2R antagonist.
BIIE0246 displaced radiolabelled neuropeptide Y from NPY2R sites on SMS-KAN cells expressing the hY2R, with an IC50 of 3.3 nM1. In addition, BIIE0246 displayed an IC50 of 7.5 nM for the displacement of [125I]-NPY from Y2R binding sites in preparations from rabbit kidney3.
The antagonistic properties of BIIE0246 were demonstrated by a concentration dependent right shift for the dose-response curve of the endogenous agonist NPY in the rat vas deferens assay – a functional bioassay for the Y2 receptor1,4.
The low nanomolar binding affinity as well as the antagonistic potency of BIIE0246 was confirmed in several different cellular and tissue/isolated organ-based assays reported in various scientific papers5-9.
| Probe name / negative control | BIIE0246 | BIIE0212 |
| MW [Da, free base]a | 896.1 | 665.9 |
| Radioligand binding hY2R (IC50) [nM]b | 3.3 | n.a. |
| Radioligand binding rabbit Y2R (IC50) [nM]c | 7.5 | 3300 |
| Radioligand binding rY1R IC50) [nM]d | >10,000 | n.a. |
| Radioligand binding rY2R IC50) [nM]d | 15 | n.a. |
| Radioligand binding rY4R IC50) [nM]d | >10,000 | n.a. |
| Radioligand binding rY5R IC50) [nM]d | >10,000 | n.a. |
| Y2 antagonistic activity in rat vas deferens bioassay (pA2)e | 8.1 | n.a. |
a for the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
b Displacement of radiolabelled NPY from SMS-KAN cells expressing human NPY2R1.
c Displacement of radiolabelled NPY from Y2R binding sites in rabbit kidney membrane preparations3.
d Displacement of radiolabelled ligands binding to HEK 293 cells transfected with rat Y1, Y2, Y4, and Y5 receptor cDNA, respectively. For details see lit.4.
e Alteration of NPY-induced inhibition of the twitch response in electrically stimulated rat vas deferens preparations by an Y2 antagonist4.
BIIE0246 is a large and flexible peptidomimetic molecule with rather poor drug-like properties, displaying low permeability, high plasma protein binding and moderate microsomal stability. Accordingly, for in vivo investigations BIIE0246 is best administered via parenteral routes.
| Probe name / negative control | BIIE0246 | BIIE0212 |
| logD @ pH 2 | 2.2 | 1.5 |
| Solubility @ pH 2.2 | pH 4.4 | pH 6.8 [µg/mL] | 206 | 26 | 20 | 166 | 82 | — |
| PAMPA permeability [10-6 cm · s-1] | 0.005 | 0.01 |
| Caco-2 permeability AB @ pH 7.4 [10-6 cm · s-1] | <0.86 | 3.5 |
| Caco-2 efflux ratio | >1.1 | 1.3 |
| MDCK permeability PappAB @ 1µM [10-6 cm ⋅ s-1] | Pa-b: <0.2 | Pa-b: <0.23 |
| MDCK efflux ratio | >1.1 | >1.1 |
| Microsomal stability (human/mouse/rat) [% QH] | 62 / 40 / 66 | 74 / 61 / 79 |
| Hepatocyte stability (human/mouse/rat) [% QH] | 5 / 26 / 38 | 15 / 61 / 54 |
| Plasma Protein Binding (human/rat) [%] | 99.0 / 99.4 | 99.1 / 99.4 |
| hERG (IC50) [µM] | > 0.1 | > 0.3 |
| CYP 3A4 (IC50) [µM] | 3.2 | 8.6 |
| CYP 2C8 (IC50) [µM] | 10.9 | 18.9 |
| CYP 2C9 (IC50) [µM] | > 50 | 46.7 |
| CYP 2C19 (IC50) [µM] | > 50 | > 50 |
| CYP 2D6 (IC50) [µM] | 20.4 | 24.1 |
BIIE0246 was used as a subtype selective pharmacological tool in several in vivo studies to investigate the (patho-) physiological role of Y2 receptor modulation in various tissues – including CNS10-15. However, the duration of action after i.v. or i.p. application is rather short (in mice a half-life of < 3h was estimated15). Central availability of BIIE0246 after systemic administration was shown to be limited (brain to plasma ratio: 0.2 % 30 min after i.p. dosing16); hence, for the study of central Y2R mediated effects BIIE0246 was administered intrathecally or injected directly into the brain region of interest11.
BIIE0212 is a congeneric analogue from the same series of L-argininamides with similar physicochemical properties but with a more than 400-fold lower affinity towards the Y2 receptor3.
BIIE0212 which serves as a negative control
BIIE0246 features an excellent subtype selectivity as indicated by a >600 fold lower affinity in rat Y1, Y4 and Y5 radioligand binding assays. No bioactivity was seen in a panel of 60 other receptor types or enzymes1. Screening against a panel of 40 CNS targets revealed submicromolar affinity only in case of the α1A adrenergic receptor and the μ- and κ-opiod receptors16.
| SELECTIVITY DATA AVILABLE | BIIE0246 | BIIE0212 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BIIE0246_selectivityData.xlsx
BIIE0212_selectivityData.xlsx
Structurally BIIE0246 is an L-arginine derivative mimicking the C-terminal RQRYamide motif of the endogenous signal peptides NPY and peptide YY (PYY).
JNJ-520778717, JNJ3102002818,19, [3H]UR-PLN19620, Cpd. 36 (GSK)21, Cpd. 2 (GSK)22, CYM 9484 and CYM 955223, SF-1124, ML05225, and ML07525 can serve as reference molecules.
BIIE0246 is a highly potent, non-peptide, competitive neuropeptide Y (NPY) Y2 receptor selective antagonist. A low-affinity congener is available as a negative control.
Neue substituierte Aminosäurederivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen.
Dollinger H., Doods H., Esser F., Gaida W., Mihm G., Rudolf K., Schnorrenberg G.
DE19816929.
Establishment of robust functional assays for the characterization of neuropeptide Y (NPY) receptors: identification of 3-(5-benzoyl-thiazol-2-ylamino)-benzonitrile as selective NPY type 5 receptor antagonist.
Dautzenberg F. M., Higelin J., Pflieger P., Neidhart W., Guba W.
Neuropharmacology. 2005, 48, 1043–55.
Blockade of the Neuropeptide Y Y2 Receptor with the Specific Antagonist BIIE0246 Attenuates the Effect of Endogenous and Exogenous Peptide YY(3-36) on Food Intake.
Abbott C. R., Small C. J., Kennedy A. R., Neary N. M., Sajedi A., Ghatei M. A., Bloom S. R.
Brain Res 2005, 1043, (1–2), 139–144.
Peripherally Administered Y2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice with Excess Neuropeptide Y, but Enhances Obesity in Control Mice.
Ailanen L., Vähätalo L. H., Salomäki-Myftari H., Mäkelä S., Orpana W., Ruohonen S. T., Savontaus E.
Front Pharmacol 2018, 9, 319/1.
Characterization of N-(1-Acetyl-2,3-Dihydro-1H-Indol-6-Yl)-3-(3-Cyano-Phenyl)-N-[1-(2-Cyclopentyl-Ethyl)-Piperidin-4yl]Acrylamide (JNJ-5207787), a Small Molecule Antagonist of the Neuropeptide Y Y2 Receptor.
Bonaventure P., Nepomuceno D., Mazur C., Lord B., Rudolph D. A., Jablonowski J. A., Carruthers N. I., Lovenberg T. W.
J Pharmacol Exp Ther 2014, 308, (3), 1130–1137.
In Vitro and in Vivo Characterization of JNJ-31020028 (N-(4-{4-[2-(Diethylamino)-2-Oxo-1-Phenylethyl]Piperazin-1-Yl}-3-Fluorophenyl)-2-Pyridin-3-Ylbenzamide), a Selective Brain Penetrant Small Molecule Antagonist of the Neuropeptide Y Y2 Receptor.
Shoblock J. R, Welty N., Nepomuceno D., Lord B., Aluisio L., Fraser I., Motley S. T., Sutton S. W., Morton K., Galici R., Atack J. R., Dvorak L., Swanson D. M., Carruthers N. I., Dvorak C., Lovenberg T. W., Bonaventure P.
Psychopharmacology 2009, 208, (2), 265.
The Discovery and Synthesis of JNJ 31020028, a Small Molecule Antagonist of the Neuropeptide Y Y2 Receptor.
Swanson D. M., Wong V. D., Jablonowski J. A., Shah C., Rudolph D. A., Dvorak C. A., Seierstad M., Dvorak L. K., Morton K., Nepomuceno D., Atack J. R., Bonaventure P., Lovenberg T. W., Carruthers N. I.
Bioorg Med Chem Lett 2011, 21, (18), 5552–5556.
The Identification and Optimisation of Novel and Selective Diamide Neuropeptide Y Y2 Receptor Antagonists.
Lunniss G. E., Barnes A. A., Barton N., Biagetti M., Bianchi F., Blowers S. M., Caberlotto L., Emmons A., Holmes I. P., Montanari D., Norris R., Walters D. J., Watson S. P.
Bioorg Med Chem Lett 2009, 19, (15), 4022–4025.
The Identification of a Series of Novel, Soluble Non-Peptidic Neuropeptide Y Y2 Receptor Antagonists.
Lunniss G. E., Barnes A. A., Barton N., Biagetti M., Bianchi F., Blowers S. M., Caberlotto L. L., Emmons A., Holmes I. P., Montanari D., Norris R., Puckey G. V., Walters D. J., Watson S. P., Willis J.
Bioorg Med Chem Lett 2010, 20, (24), 7341–7344.
When you plan a publication, please use the following acknowledgement:
BIIE0246 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.