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GR 94800

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GR 94800 is a potent and selective tachykinin NK2 receptor antagonist (pKB = 9.6, 6.4 and 6.0 for NK2, NK1 and NK3 receptors, respectively).

Category
Peptide Inhibitors
Catalog number
BAT-010258
CAS number
141636-65-9
Molecular Formula
C49H61N9O8
Molecular Weight
904.08
GR 94800
IUPAC Name
(2S)-N-[(2S)-1-amino-1-oxohexan-2-yl]-1-[(2R)-1-[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-benzamidopropanoyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxamide
Synonyms
N-Benzoyl-L-alanyl-L-alanyl-D-tryptophyl-L-phenylalanyl-D-prolyl-L-prolyl-L-norleucinamide
Appearance
White Powder
Purity
>98%
Density
1.282 g/cm3
Boiling Point
1310.4°C at 760 mmHg
Sequence
AAWFPPX
Storage
Store at -20°C
InChI
InChI=1S/C49H61N9O8/c1-4-5-21-37(42(50)59)54-47(64)40-23-14-25-57(40)49(66)41-24-15-26-58(41)48(65)39(27-32-16-8-6-9-17-32)56-46(63)38(28-34-29-51-36-22-13-12-20-35(34)36)55-44(61)31(3)52-43(60)30(2)53-45(62)33-18-10-7-11-19-33/h6-13,16-20,22,29-31,37-41,51H,4-5,14-15,21,23-28H2,1-3H3,(H2,50,59)(H,52,60)(H,53,62)(H,54,64)(H,55,61)(H,56,63)/t30-,31-,37-,38+,39-,40-,41+/m0/s1
InChI Key
CWEISCOCKRHHOU-UJYVDGJVSA-N
Canonical SMILES
CCCCC(C(=O)N)NC(=O)C1CCCN1C(=O)C2CCCN2C(=O)C(CC3=CC=CC=C3)NC(=O)C(CC4=CNC5=CC=CC=C54)NC(=O)C(C)NC(=O)C(C)NC(=O)C6=CC=CC=C6
1.NK1- and NK3-receptor mediated inhibition of 5-hydroxytryptamine release from the vascularly perfused small intestine of the guinea-pig.
Ginap T;Kilbinger H Naunyn Schmiedebergs Arch Pharmacol. 1997 Nov;356(5):689-93.
The effects of tachykinins on the spontaneous release of 5-hydroxytryptamine (5-HT) from the enterochromaffin cells into the portal circulation was investigated in vitro using the vascularly perfused isolated guinea-pig small intestine. 5-HT was determined by HPLC with electrochemical detection. Test substances were applied intraarterially. Substance P (SP) caused a concentration-dependent decrease in 5-HT outflow with an EC50 of 50 pmol/l. Similarly, the selective NK1 receptor agonist SP methyl ester (1 nmol/l) significantly inhibited 5-HT outflow (to 51 +/- 3%). When tetrodotoxin (1 mumol/l) was added to the arterial perfusion medium, the inhibition by SP of 5-HT outflow was not affected. The selective NK1 receptor antagonist CP 99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] (0.1 mumol/l) prevented the inhibitory effect of SP (0.1 mumol/l). Neither GR 94800 (PhCO-Ala-Ala-DTrp-Phe-DPro-Pro-NleNH2) (0.1 mumol/l) nor SR 142801 [(S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N- methylacetamide] (10 nmol/l), which are selective NK2 and NK3 receptor antagonists, changed the SP-mediated inhibition. The selektive NK3 receptor agonist senktide (10 nmol/l) also decreased the 5-HT outflow (to 57 +/- 5%).
2.An investigation of tachykinin NK2 receptor subtypes in the rat.
Matuszek MA;Zeng XP;Strigas J;Burcher E Eur J Pharmacol. 1998 Jul 3;352(1):103-9.
The heterogeneity of tachykinin NK2 receptor subtypes was examined in five tissues from the rat, using binding and functional techniques. Initial experiments with the selective radioligand [125I][Lys5,Tyr(I2)7,MeLeu9,Nle10]neurokinin A-(4-10) showed no specific binding to rat spinal cord membranes or sections. However, this radioligand exhibited high specific binding (80-95% of total) in membranes from the rat fundus, colon, bladder and vas deferens. Dissociation constants (KD) were lower in bladder and colon (0.4 nM) than in fundus (1.9 nM) or vas deferens (1.4 nM). Neurokinin A, neuropeptide gamma, [Lys5,MeLeu9,Nle10]NK(4-10), SR 48968 [(S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophen yl)butyl]benzamine], GR 94800 [PhCO-Ala-Ala-DTrp-Phe-DPro-Pro-Nle-NH2] and MEN 10627 [cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2beta-5beta)] displayed high affinity (pIC50 8.4-9.5) as competitors, with no significant difference in potency between these four tissues. [Lys5,MeLeu9,Nle10]neurokinin A-(4-10) contracted the isolated fundus (EC50 117 nM) and bladder (EC50 10 nM) and these responses were similarly inhibited by the tachykinin NK2 receptor antagonists, SR 48968 and MEN 10627 (pA2 values 7.
3.Characterization of tachykinin NK2 receptors in human urinary bladder.
Zeng XP;Moore KH;Burcher E J Urol. 1995 May;153(5):1688-92.
Functional and radioligand binding studies with selective agonists and antagonists were used to investigate tachykinin receptors in the human bladder. Strips of detrusor muscle were contracted by the tachykinins neurokinin A and neuropeptide gamma, and by the NK2 receptor selective agonists [Lys5,MeLeu9,Nle10]-NKA(4-10) and [Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4- 10), with pD2 values 8.2, 8.0, 8.1 and 7.1. [Sar9,Met(O2)11]-SP and senktide were ineffective agonists, indicating an absence of NK1 and NK3 receptors. The contractile responses to [Lys5,MeLeu9,Nle10]-NKA(4-10) were inhibited competitively by the NK2 receptor selective antagonists SR 48968, GR 94800 and MDL 29913, with pA2 values 9.1, 8.6 and 7.0. Specific binding of the new NK2 receptor selective radioligand [125I]-[Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10) was saturable to a high affinity site (KD 2.3 nM.). Specific binding was inhibited by NK2 receptor agonists and antagonists, but not by NK1 and NK3 analogues, showing binding to NK2 receptors only. These data indicate that NK2 receptors may be involved in regulation of detrusor contractility in the human bladder.
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