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VIP Antagonist

* Please kindly note that our products are not to be used for therapeutic purposes and cannot be sold to patients.

VIP antagonist, a hybrid of neurotensin (6-11) and VIP (7-28), is a competitive antagonist of VIP-binding to glial cells. In rats with reduced masculine potency, it significantly inhibits VIP-stimulated sexual behavior. It antagonizes VIP receptors on non-small cell lung cancer cells, thereby inhibiting tumor growth in vivo and in vitro.

Category

Peptide Inhibitors

Catalog number

BAT-015215

CAS number

125093-93-8

Molecular Formula

C154H257N49O40S

Molecular Weight

3467.06

Specification
Reference Reading

IUPAC Name

(3S)-4-[[(2S)-4-amino-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1,4-diamino-1,4-dioxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-[[(2S,3R)-2-[[(2S)-2-[[(2S)-1-[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2S)-1-[(2S)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxybutanoyl]amino]-4-oxobutanoic acid

Synonyms

[Lys1,Pro2,5,Arg3,4,Tyr6]VIP, human, porcine, rat, ovine; H-Lys-Pro-Arg-Arg-Pro-Tyr-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2; L-lysyl-L-prolyl-L-arginyl-L-arginyl-L-prolyl-L-tyrosyl-L-threonyl-L-alpha-aspartyl-L-asparagyl-L-tyrosyl-L-threonyl-L-arginyl-L-leucyl-L-arginyl-L-lysyl-L-glutaminyl-L-methionyl-L-alanyl-L-valyl-L-lysyl-L-lysyl-L-tyrosyl-L-leucyl-L-asparagyl-L-seryl-L-isoleucyl-L-leucyl-L-asparaginamide; [Lys1,Pro2,5,Arg3,4,Tyr6]-Vasoactive Intestinal Peptide human, porcine, rat

Appearance

White Powder

Purity

95%

Sequence

KPRRPYTDNYTRLRKQMAVKKYLNSILN-NH2

Storage

Store at -20°C

Solubility

Soluble in Water

InChI

InChI=1S/C154H257N49O40S/c1-15-81(10)120(146(239)195-104(68-79(6)7)134(227)187-101(123(164)216)72-115(161)211)199-142(235)111(76-204)197-138(231)109(74-117(163)213)192-135(228)103(67-78(4)5)189-136(229)105(69-85-40-46-88(207)47-41-85)190-130(223)93(32-18-22-57-157)179-127(220)94(33-19-23-58-158)184-145(238)119(80(8)9)198-124(217)82(11)177-125(218)99(54-65-244-14)182-132(225)98(52-53-114(160)210)181-126(219)92(31-17-21-56-156)178-128(221)95(34-24-59-173-151(165)166)180-133(226)102(66-77(2)3)188-131(224)97(36-26-61-175-153(169)170)185-147(240)121(83(12)205)200-140(233)106(70-86-42-48-89(208)49-43-86)191-137(230)108(73-116(162)212)193-139(232)110(75-118(214)215)196-148(241)122(84(13)206)201-141(234)107(71-87-44-50-90(209)51-45-87)194-144(237)113-39-29-64-203(113)150(243)100(37-27-62-176-154(171)172)186-129(222)96(35-25-60-174-152(167)168)183-143(236)112-38-28-63-202(112)149(242)91(159)30-16-20-55-155/h40-51,77-84,91-113,119-122,204-209H,15-39,52-76,155-159H2,1-14H3,(H2,160,210)(H2,161,211)(H2,162,212)(H2,163,213)(H2,164,216)(H,177,218)(H,178,221)(H,179,220)(H,180,226)(H,181,219)(H,182,225)(H,183,236)(H,184,238)(H,185,240)(H,186,222)(H,187,227)(H,188,224)(H,189,229)(H,190,223)(H,191,230)(H,192,228)(H,193,232)(H,194,237)(H,195,239)(H,196,241)(H,197,231)(H,198,217)(H,199,235)(H,200,233)(H,201,234)(H,214,215)(H4,165,166,173)(H4,167,168,174)(H4,169,170,175)(H4,171,172,176)/t81-,82-,83+,84+,91-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,119-,120-,121-,122-/m0/s1

InChI Key

FBYWUGLFWCEKAN-KQQCXCAZSA-N

Canonical SMILES

CCC(C)C(C(=O)NC(CC(C)C)C(=O)NC(CC(=O)N)C(=O)N)NC(=O)C(CO)NC(=O)C(CC(=O)N)NC(=O)C(CC(C)C)NC(=O)C(CC1=CC=C(C=C1)O)NC(=O)C(CCCCN)NC(=O)C(CCCCN)NC(=O)C(C(C)C)NC(=O)C(C)NC(=O)C(CCSC)NC(=O)C(CCC(=O)N)NC(=O)C(CCCCN)NC(=O)C(CCCNC(=N)N)NC(=O)C(CC(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)C(C(C)O)NC(=O)C(CC2=CC=C(C=C2)O)NC(=O)C(CC(=O)N)NC(=O)C(CC(=O)O)NC(=O)C(C(C)O)NC(=O)C(CC3=CC=C(C=C3)O)NC(=O)C4CCCN4C(=O)C(CCCNC(=N)N)NC(=O)C(CCCNC(=N)N)NC(=O)C5CCCN5C(=O)C(CCCCN)N

1. An antagonist to vasoactive intestinal peptide affects cellular functions in the central nervous system

I Gozes, D E Brenneman, S K McCune, M Fridkin, T W Moody, L Jacobson, D Warren J Pharmacol Exp Ther . 1991 Jun;257(3):959-66.

A vasoactive intestinal peptide (VIP) antagonist was synthesized and used to investigate the interactions of VIP with its receptors present in the central nervous system (CNS). The VIP antagonist is a hybrid peptide consisting of a portion of VIP and a portion of neurotensin, designed to change the membrane permeability of the VIP portion. The hybrid antagonist displaced 80 to 90% of [125I]VIP binding to cell cultures from cerebral cortex, hippocampus or spinal cord. The displacement curve was biphasic, suggesting two binding sites. In the case of cortical astrocytes, the antagonist had a Ki of 45 pM at one site and a Ki of 74 nM at the other. At the lower affinity binding site, the antagonist was about 10-fold more potent than VIP in displacing radiolabeled VIP. The accumulation of cyclic AMP (cAMP) in VIP-stimulated cortical glia cultures was decreased by the new antagonist (EC50, 59 nM). This decrease in cAMP was greater than that achieved in the presence of other putative VIP antagonists. Finally, the addition of 1 nM hybrid antagonist to dissociated spinal cord cultures resulted in a 42% reduction in neuronal cell counts as compared with controls, and the EC50 of this effect was about 30 pM, which corresponded closely to the Ki of antagonist displacement of [125I]VIP binding at the high-affinity site. The antagonist appears to be a competitive blocker for both VIP-mediated increases in cAMP formation or VIP-associated maintenance of neuronal survival in spinal cord cultures. Thus, we describe a potent VIP antagonist which interacts with two functionally distinct VIP receptors in the CNS.

2. Study of species specificity in growth hormone-releasing factor (GRF) interaction with vasoactive intestinal peptide (VIP) receptors using GRF and intestinal VIP receptors from rat and human: evidence that Ac-Tyr1hGRF is a competitive VIP antagonist in the rat

C Rouyer-Fessard, A Couvineau, M Laburthe Mol Pharmacol . 1986 Jan;29(1):23-7.

In order to determine species specificity in growth hormone-releasing factor (GRF) interaction with vasoactive intestinal polypeptide (VIP) receptors, we have tested rat (r) GRF (with a His1 such as in VIP), human (h) GRF and position 1 substituted analogs of hGRF (Ala1, Ac-Tyr1, His1, Phe1, and Trp1 in the place of Tyr1) for their ability to inhibit 125I-VIP binding and to stimulate adenylate cyclase activity in human and rat intestinal epithelial membranes. We show that rGRF has a much higher affinity than hGRF for both human and rat VIP receptors. In humans, the Ki values for inhibiting 125I-VIP binding are 0.5 (VIP), 26 (rGRF), and 830 nM (hGRF). In rats the values are 0.6 (VIP), 46 (rGRF), and 1100 nM (hGRF). This is due in part to the presence of His1 in rGRF since the analog His1 hGRF has a higher affinity than hGRF in man and rat, i.e., Ki = 320 nM and 460 nM, respectively. Studies of adenylate cyclase stimulation reveal that rGRF and His1 hGRF are full VIP agonists in man and rat, whereas hGRF and its other analogs behave as partial agonists in both species. One of the hGRF analogs tested (Ac-Tyr1hGRF) is of great interest since it inhibits 125I-VIP binding to rat intestinal membranes with a Ki = 430 nM but has a negligible intrinsic activity in stimulating adenylate cyclase activity (about 6% of the efficacy of VIP). This analog does inhibit the VIP-stimulated adenylate cyclase activity in a dose-dependent manner, complete inhibition of the VIP (0.01-1 nM) effect being obtained with 30 microM analog. The Schild plot of the inhibitory effect further indicates competitive antagonism. In contrast, Ac-Tyr1hGRF is a partial VIP agonist in humans (about 20% of the efficacy of VIP). These results evidence the important role of His1 for peptide interaction with VIP receptors and provide the first example of a competitive VIP antagonist.

3. VIP is involved in peripheral CRF-induced stimulation of propulsive colonic motor function and diarrhea in male rats

Yvette Taché, Lixin Wang, Hiroshi Karasawa, Kazuhiko Koike, Seiichi Yakabi, Koji Yakabi, Pu-Qing Yuan Am J Physiol Gastrointest Liver Physiol . 2018 May 1;314(5):G610-G622. doi: 10.1152/ajpgi.00308.2017.

We investigated whether vasoactive intestinal peptide (VIP) and/or prostaglandins contribute to peripheral corticotropin-releasing factor (CRF)-induced CRF1receptor-mediated stimulation of colonic motor function and diarrhea in rats. The VIP antagonist, [4Cl-D-Phe6, Leu17]VIP injected intraperitoneally completely prevented CRF (10 µg/kg ip)-induced fecal output and diarrhea occurring within the first hour after injection, whereas pretreatment with the prostaglandins synthesis inhibitor, indomethacin, had no effect. In submucosal plexus neurons, CRF induced significant c-Fos expression most prominently in the terminal ileum compared with duodenum and jejunum, whereas no c-Fos was observed in the proximal colon. c-Fos expression in ileal submucosa was colocalized in 93.4% of VIP-positive neurons and 31.1% of non-VIP-labeled neurons. CRF1receptor immunoreactivity was found on the VIP neurons. In myenteric neurons, CRF induced only a few c-Fos-positive neurons in the ileum and a robust expression in the proximal colon (17.5 ± 2.4 vs. 0.4 ± 0.3 cells/ganglion in vehicle). The VIP antagonist prevented intraperitoneal CRF-induced c-Fos induction in the ileal submucosal plexus and proximal colon myenteric plexus. At 60 min after injection, CRF decreased VIP levels in the terminal ileum compared with saline (0.8 ± 0.3 vs. 2.5 ± 0.7 ng/g), whereas VIP mRNA level detected by qPCR was not changed. These data indicate that intraperitoneal CRF activates intestinal submucosal VIP neurons most prominently in the ileum and myenteric neurons in the colon. It also implicates VIP signaling as part of underlying mechanisms driving the acute colonic secretomotor response to a peripheral injection of CRF, whereas prostaglandins do not play a role. NEW & NOTEWORTHY Corticotropin-releasing factor (CRF) in the gut plays a physiological role in the stimulation of lower gut secretomotor function induced by stress. We showed that vasoactive intestinal peptide (VIP)-immunoreactive neurons in the ileal submucosal plexus expressed CRF1receptor and were prominently activated by CRF, unlike colonic submucosal neurons. VIP antagonist abrogated CRF-induced ileal submucosal and colonic myenteric activation along with functional responses (defecation and diarrhea). These data point to VIP signaling in ileum and colon as downstream effectors of CRF.