BIIE 0246

BIIE 0246 is a potent and selective antagonist of neuropeptide Y Y2 receptor with IC50 value of 3.3 nM [1].

Neuropeptide Y Y2 receptor (Y2R) is a G-protein-coupled receptor for neuropeptide Y (NPY), which is widely distributed in the peripheral and central nervous system. Y2R mediates the presynaptic inhibitory effect [2].

BIIE 0246 is a potent and selective Y2R antagonist. In rat hippocampal slices, BIIE0246 (100 nM) suppressed the inhibition of primary afterdischarge activity induced by NPY and [ahx5-24]NPY. Also, BIIE0246 suppressed the inhibitory effects of NPY and [ahx5-24]NPY, which inhibited the population excitatory postsynaptic potential (pEPSP) evoked by stratum radiatum stimulation in area CA1 [2]. In HEK293 cells transfected with the rat Y2 receptor, BIIE0246 exhibited high affinity for specific PYY3-36 binding sites with Ki values of 8-15 nM. In the rat colon, BIIE0246 (1 μM) completely blocked PYY3-36-induced contraction response [3].

In rats, BIIE0246 (1 nM) attenuated the reduction in feeding induced by PYY(3-36) (7.5 nmol/kg). In satiated rats, BIIE0246 significantly increased feeding. These results suggested that Y2R played a critical role in post-prandial satiety [4]. In the elevated plus-maze, BIIE0246 exhibited anxiolytic-like effect [5].

References:
[1].  Doods H, Gaida W, Wieland HA, et al. BIIE0246: a selective and high affinity neuropeptide Y Y(2) receptor antagonist. Eur J Pharmacol, 1999, 384(2-3): R3-5.
[2].  El Bahh B, Cao JQ, Beck-Sickinger AG, et al. Blockade of neuropeptide Y(2) receptors and suppression of NPY's anti-epileptic actions in the rat hippocampal slice by BIIE0246. Br J Pharmacol, 2002, 136(4): 502-509.
[3].  Dumont Y, Cadieux A, Doods H, et al. BIIE0246, a potent and highly selective non-peptide neuropeptide Y Y(2) receptor antagonist. Br J Pharmacol, 2000, 129(6): 1075-1088.
[4].  Abbott CR, Small CJ, Kennedy AR, et al. 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. Brain Res, 2005, 1043(1-2): 139-144.
[5].  Bacchi F, Mathé AA, Jiménez P, et al. Anxiolytic-like effect of the selective neuropeptide Y Y2 receptor antagonist BIIE0246 in the elevated plus-maze. Peptides, 2006, 27(12): 3202-3207.

Antagonistic interaction between BIIE 0246, a neuropeptide Y Y2-receptor antagonist, and omega-conotoxin GVIA, a Ca2+ channel antagonist, in presynaptic transmitter releases in dog splenic arteries.[Pubmed:12120763]

Jpn J Pharmacol. 2002 Jun;89(2):188-91.

Isolated dog splenic arteries were perfused with Krebs-Henseleit solution at 37 degrees C, using the cannula inserting method. Periarterial nerve electrical stimulation (10-V amplitude; 1-ms duration; 30-s trains of pulses; 1, 4 and 10 Hz) readily caused double peaked vasoconstrictions, i.e., 1st peaked response was mostly inhibited by alpha,beta-methylene ATP and the 2nd one, by prazosin. These responses were consistently inhibited by omega-conotoxin GVIA (omega-CTX), whereas they were facilitated by BIIE 0246, a neuropeptide Y (NPY) Y2-receptor antagonist. The omega-CTX-induced blocking effects of transmitter release were significantly antagonized by BIIE 0246. It is possible that the NPY Y2 receptor activity may partially be linked to presynaptic Ca2+ channels.

Vascular pharmacology of BIIE0246, the first selective non-peptide neuropeptide Y Y(2) receptor antagonist, in vivo.[Pubmed:11487518]

Br J Pharmacol. 2001 Aug;133(7):1073-80.

BIIE0246, a recently introduced non-peptide neuropeptide Y (NPY) Y(2) receptor antagonist, was pharmacologically characterized in vivo, on vascular responses evoked in the anaesthetized pig. The NPY Y(2) receptor agonist N-acetyl[Leu(28)Leu(31)]NPY(24-36) evoked dose-dependent vasoconstriction in spleen. These vascular responses were potently and dose-dependently antagonized by BIIE0246. Significant inhibition was seen already at 1 nmol kg(-1), whereas at 100 nmol kg(-1) of BIIE0246 these responses were completely abolished. The ID(50) value for this antagonism was 2.1 nmol kg(-1). Peptide YY (PYY) evoked dose-dependent vasoconstriction in both kidney and spleen, vascular responses mediated by the NPY Y(1) receptor and both NPY Y(1) and Y(2) receptors, respectively. Only the splenic response was inhibited by BIIE0246, the effect of which reached significance at 1 nmol kg(-1). Already 30 min after the last dose of BIIE0246 there was a significant recovery of the PYY-evoked splenic vasoconstriction, and a further 60 min later, this response was no longer significantly inhibited compared to control. BIIE0246 (100 nmol kg(-1)) did not affect renal and splenic vasoconstrictor responses either to the NPY Y(1) receptor agonist [Leu(31)Pro(34)]NPY, the alpha(1)-adrenoceptor agonist phenylephrine, the P2X(1)-purinoceptor agonist alpha,beta-methylene ATP or angiotensin II, demonstrating both selectivity and specificity for the NPY Y(2) receptor in vivo. It is concluded that BIIE0246 is a highly potent and selective NPY Y(2) receptor antagonist, albeit with rather short duration of action, in vivo. BIIE0246 thus represents the first interesting tool for studies on NPY Y(2) receptor-mediated transmission in vivo.

BIIE0246, a potent and highly selective non-peptide neuropeptide Y Y(2) receptor antagonist.[Pubmed:10725255]

Br J Pharmacol. 2000 Mar;129(6):1075-88.

1. BIIE0246, a newly synthesized non-peptide neuropeptide Y (NPY) Y(2) receptor antagonist, was able to compete with high affinity (8 to 15 nM) for specific [(125)I]PYY(3 - 36) binding sites in HEK293 cells transfected with the rat Y(2) receptor cDNA, and in rat brain and human frontal cortex membrane homogenates. 2. Interestingly, in rat brain homogenates while NPY, C2-NPY and PYY(3 - 36) inhibited all specific [(125)I]PYY(3 - 36) labelling, BIIE0246 failed to compete for all specific binding suggesting that [(125)I]PYY(3 - 36) recognized, in addition to the Y(2) subtype, another population of specific NPY binding sites, most likely the Y(5) receptor. 3. Quantitative receptor autoradiographic data confirmed the presence of [(125)I]PYY(3 - 36)/BIIE0246-sensitive (Y(2)) and-insensitive (Y(5)) binding sites in the rat brain as well as in the marmoset monkey and human hippocampal formation. 4. In the rat vas deferens and dog saphenous vein (two prototypical Y(2) bioassays), BIIE0246 induced parallel shifts to the right of NPY concentration-response curves with pA(2) values of 8.1 and 8.6, respectively. In the rat colon (a Y(2)/Y(4) bioassay), BIIE0246 (1 microM) completely blocked the contraction induced by PYY(3 - 36), but not that of [Leu(31), Pro(34)]NPY (a Y(1), Y(4) and Y(5) agonist) and hPP (a Y(4) and Y(5) agonist). Additionally, BIIE0246 failed to alter the contractile effects of NPY in prototypical Y(1) in vitro bioassays. 5. Taken together, these results demonstrate that BIIE0246 is a highly potent, high affinity antagonist selective for the Y(2) receptor subtype. It should prove most useful to establish further the functional role of the Y(2) receptor in the organism.

BIIE0246: a selective and high affinity neuropeptide Y Y(2) receptor antagonist.[Pubmed:10611450]

Eur J Pharmacol. 1999 Nov 19;384(2-3):R3-5.

The in vitro biological characterisation of the first potent and selective non-peptide neuropeptide Y Y(2) receptor antagonist, (S)-N(2)-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b, e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl] cylopentyl] acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2, 4-triazol-4-yl]ethyl]-argininamid (BIIE0246) is reported. BIIE0246 displaced [125I]neuropeptide Y with high affinity (IC(50)=3.3 nM) from the human neuropeptide Y Y(2) receptor and proved to be highly selective. BIIE0246 displayed antagonistic properties and thus represents the first selective non-peptide neuropeptide Y Y(2) receptor antagonist.