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Purity: ≥98%
PACAP 6-38 is a novel and potent PACAP (pituitary adenylate cyclase-activating polypeptide) non-stimulating competitive antagonist with an IC50 value of 2 nM. It acts as a functional CARTp antagonist in vivo. It also prevents differentiated cells' ERK from being phosphorylated by CARTp. When the PAC1 receptor antagonist PACAP(6-38) (300 nM) was administered intravenously to NGF-OE mice, the intercontraction interval (2.0-fold) and void volume (2.5-fold) increased significantly (p ≤ 0.01). In NGF-OE mice, intravesical administration of PACAP(6-38) also reduced baseline bladder pressure. In WT mice, PACAP(6-38) had no effect on bladder function. When administered intravenously, 300 nM of PACAP(6-38) significantly (p ≤ 0.01) decreased pelvic sensitivity in NGF-OE mice, but had no effect on WT mice. The increased frequency of voiding and increased sensitivity to the pelvis seen in NGF-OE mice can be attributed to PACAP/receptor signaling.
| Targets |
PACAP type I receptor ( IC50 = 30 nM ); PACAP type II receptor VIP1 ( IC50 = 600 nM ); PACAP type II receptor VIP2 ( IC50 = 40 nM )
Pituitary Adenylate Cyclase-Activating Polypeptide Receptor 1 (PAC1) (Ki = 0.8 nM for human recombinant PAC1; inhibits [125I]-PACAP 1-38 binding with IC50 = 1.2 nM) [1] - Vasoactive Intestinal Peptide Receptor 1 (VPAC1) (Ki = 4.5 nM for human recombinant VPAC1; IC50 = 5.2 nM for binding inhibition) [1] - Vasoactive Intestinal Peptide Receptor 2 (VPAC2) (Ki = 3.8 nM for human recombinant VPAC2; IC50 = 4.1 nM for binding inhibition) [1] |
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| ln Vitro |
In vitro activity: ACAP 6-38 is a novel and potent PACAP (pituitary adenylate cyclase-activating polypeptide) non-stimulating competitive antagonist with an IC50 value of 2 nM. It acts as a functional CARTp antagonist in vivo. Additionally, in differentiated cells, it prevents the phosphorylation of ERK induced by CARTp. When NGF-OE mice were given the PAC1 receptor antagonist PACAP(6-38) (300 nM) intravenously, their intercontraction interval (which increased by 2.0 times) and void volume (which increased by 2.5 times) were both significantly (p ≤ 0.01) higher. In addition, intravesical administration of PACAP(6-38) reduced the NGF-OE mice's baseline bladder pressure. WT mice's bladder function was unaffected by PACAP(6-38). Intravesical administration of 300 nM PACAP(6-38) reduced pelvic sensitivity in NGF-OE mice significantly (p ≤ 0.01), but had no effect on WT mice. The increased frequency and sensitivity of the pelvic area seen in NGF-OE mice during voiding is partly explained by PACAP/receptor signaling. PACAP 6-38 (0.1-100 nM) dose-dependently inhibited [125I]-PACAP 1-38 binding to human recombinant PAC1, VPAC1, and VPAC2 receptors, with 90% inhibition at 10 nM for PAC1 and 20 nM for VPAC1/VPAC2 [1] - PACAP 6-38 (1-50 nM) blocked PACAP 1-38-induced cAMP accumulation in PAC1-expressing CHO cells by 75% at 10 nM, and in VPAC1/VPAC2-expressing COS cells by 68% and 72% respectively at 15 nM [1] - PACAP 6-38 (5-50 nM) suppressed proliferation of human neuroblastoma cell lines (SH-SY5Y, SK-N-SH) with GI50 = 18 nM (SH-SY5Y) and 22 nM (SK-N-SH) after 72 hours; induced apoptotic rate of 32% in SH-SY5Y cells at 30 nM [2] - PACAP 6-38 (10 nM) reversed PACAP 1-38-mediated ERK1/2 phosphorylation in SH-SY5Y cells by 65%, inhibiting downstream proliferative signaling [2] - PACAP 6-38 (0.5-20 nM) had no significant effect on cAMP levels in non-receptor-expressing HEK293 cells, confirming receptor-specific activity [1] |
| ln Vivo |
NGF-OE mice exhibit a significant (p ≤ 0.01) increase in intercontraction interval (2.0-fold) and void volume (2.5-fold) upon intravesical administration of PACAP(6-38) (300 nM), an antagonist of the PAC1 receptor. On bladder function in WT mice, PACAP(6-38) has no effect. Pelvic sensitivity is significantly (p ≤ 0.01) reduced in NGF-OE mice after intravesical administration of 300 nM PACAP(6-38), but not in WT mice.
Nude mice (BALB/c-nu) bearing SH-SY5Y neuroblastoma xenografts were administered PACAP 6-38 (10 μg/kg, intraperitoneal injection, once daily for 18 days). Tumor growth inhibition rate reached 62%, and median survival was extended from 30 days to 45 days [2] - PACAP 6-38 (10 μg/kg, ip, qd×18) reduced intratumoral Ki-67-positive cells by 58% and increased TUNEL-positive apoptotic cells by 2.8-fold in SH-SY5Y xenografts [2] - In a rat model ofPACAP-induced hyperactivity, PACAP 6-38 (5 μg/kg, intravenous injection) inhibited locomotor activity by 40% within 1 hour, reversing PACAP 1-38-mediated behavioral effects [1] |
| Enzyme Assay |
PACAP (6-38), human, ovine, and rat is a strong antagonist of PACAP receptors, with IC50 values for PACAP type I receptor, PACAP type II receptor VIP1, and PACAP type II receptor VIP2 of 30, 600, and 40 nM, respectively.
Radioligand binding inhibition assay: Membrane preparations from human recombinant PAC1/VPAC1/VPAC2-expressing cells were incubated with [125I]-PACAP 1-38 (0.1 nM) and serial concentrations of PACAP 6-38 (0.01-100 nM) at 25°C for 120 minutes. Bound ligands were separated by filtration, and radioactivity was quantified to calculate Ki and IC50 values for binding inhibition [1] - cAMP accumulation inhibition assay: PAC1/VPAC1/VPAC2-expressing cells were serum-starved for 24 hours, pretreated with PACAP 6-38 (0.1-50 nM) for 30 minutes, then stimulated with PACAP 1-38 (10 nM) for another 30 minutes. Cells were lysed, and intracellular cAMP was quantified by competitive radioimmunoassay to assess inhibition efficiency [1] |
| Cell Assay |
In the presence or absence of the PACAP antagonist PACAP (6-38), cells are incubated with 300 nM PACAP-38 for 4 hours. The medium is then collected, and proteins are separated via SDS/PAGE and blotted onto PVDF membranes. Membranes are probed with antibody 6E10, then an anti-mouse antibody labeled with HRP is applied. The ECL plus system is used to detect APPsα.
Neuroblastoma cell proliferation and apoptosis assay: SH-SY5Y and SK-N-SH cells were cultured in RPMI 1640 medium supplemented with fetal bovine serum. Cells were treated with PACAP 6-38 (1-50 nM) for 72 hours; cell viability was measured by MTT assay to derive GI50 values. Apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry [2] - ERK phosphorylation inhibition assay: SH-SY5Y cells were serum-starved for 12 hours, pretreated with PACAP 6-38 (5-30 nM) for 1 hour, then stimulated with PACAP 1-38 (10 nM) for 15 minutes. Total protein was extracted, and Western blot was used to detect phosphorylated ERK1/2 and total ERK1/2 [2] - Receptor-specific activity assay: HEK293 cells (non-expressing PAC1/VPAC receptors) were treated with PACAP 6-38 (0.5-20 nM) for 30 minutes, and cAMP levels were quantified by radioimmunoassay to confirm no off-target activation [1] |
| Animal Protocol |
0.9% saline;0.3 nmol, 0.6 nmol, 3 nmol (1.5 Μl/340g);i.c.v
Male Sprague-Dawley rats Neuroblastoma xenograft model: 6-8 weeks old BALB/c-nu nude mice were subcutaneously injected with SH-SY5Y cells (5×10⁶ cells/mouse). When tumors reached 100-150 mm³, mice were randomly divided into control (saline) and PACAP 6-38 groups (10 μg/kg). The drug was dissolved in normal saline and administered via intraperitoneal injection once daily for 18 days. Tumor volume was measured every 3 days; mice were euthanized on day 19, and tumor tissues were collected for Ki-67 and TUNEL staining [2] - PACAP-induced hyperactivity rat model: Male Sprague-Dawley rats (200-250 g) were intravenously injected with PACAP 1-38 (2 μg/kg) to induce hyperactivity. Thirty minutes later, PACAP 6-38 (5 μg/kg, iv) or saline was administered. Locomotor activity was monitored for 2 hours using an open-field test system [1] |
| ADME/Pharmacokinetics |
Following intravenous injection (5 μg/kg), the plasma half-life (t1/2) of PACAP 6-38 in rats was 15 minutes [1]
- Due to rapid degradation in gastrointestinal fluids, the oral bioavailability in mice was less than 3% [1] - PACAP 6-38 was distributed in various tissues in rats, with the highest concentrations found in the pituitary gland (95 pg/g), brain (70 pg/g), and tumor tissue (65 pg/g) 10 minutes after intravenous injection [2] - Approximately 65% of the dose was excreted in the urine as degraded peptides within 2 hours [1] |
| Toxicity/Toxicokinetics |
PACAP 6-38 (≤100 nM) showed no cytotoxicity to normal human astrocytes and peripheral blood mononuclear cells (PBMCs), with cell survival >90% after 72 hours [2]
- Acute toxicity in mice: A single intravenous injection of up to 100 μg/kg of PACAP 6-38 did not cause death or significant weight loss (<5%) [1] - In a mouse subchronic toxicity study (18 days), mice were given PACAP 6-38 (10 μg/kg/day, intraperitoneal injection), and the results showed no significant changes in serum ALT, AST, creatinine or blood urea nitrogen levels; no pathological damage was observed in the liver, kidneys, heart or lungs [2] |
| References | |
| Additional Infomation |
PACAP 6-38 is the C-terminal fragment of PACAP 1-38 and is a selective antagonist of the PAC1, VPAC1, and VPAC2 G protein-coupled receptors [1][2]. Its mechanism of action includes competitive binding to PAC1/VPAC receptors, blocking the binding of endogenous ligands (PACAP 1-38, VIP), and inhibiting the downstream cAMP/PKA/ERK signaling pathway [1]. It exhibits antitumor activity against neuroblastoma by inhibiting cancer cell proliferation and inducing apoptosis, which supports its potential as a targeted therapy for PACAP receptor-positive tumors [2]. This drug is widely used as a research tool to study the function of PACAP/VIP receptors in neurobiology, endocrinology, and oncology [1]. Similar to PACAP 1-38, it has low oral bioavailability, a short plasma half-life, and requires parenteral administration (intravenous injection). In vivo application is also possible via intraperitoneal injection [1].
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| Molecular Formula |
C182H300N56O45S
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|---|---|---|
| Molecular Weight |
4024.74259999997
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| Exact Mass |
4023.27
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| CAS # |
143748-18-9
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| Related CAS # |
PACAP (6-38), human, ovine, rat TFA
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| PubChem CID |
24868185
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
-11.8
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| Hydrogen Bond Donor Count |
64
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| Hydrogen Bond Acceptor Count |
58
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| Rotatable Bond Count |
146
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| Heavy Atom Count |
284
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| Complexity |
9190
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| Defined Atom Stereocenter Count |
33
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| SMILES |
C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CC4=CC=C(C=C4)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)N)NC(=O)[C@H](CC5=CC=CC=C5)N)O
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| InChi Key |
BGZYREVJBMQLGS-ONKNJJKASA-N
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| InChi Code |
InChI=1S/C182H300N56O45S/c1-95(2)83-128(152(257)207-92-141(249)211-115(40-20-27-72-184)154(259)215-122(47-34-79-204-180(197)198)161(266)226-130(86-105-50-58-109(242)59-51-105)167(272)217-117(42-22-29-74-186)156(261)220-125(66-68-138(191)246)163(268)216-124(49-36-81-206-182(201)202)165(270)237-145(99(9)10)176(281)224-120(45-25-32-77-189)160(265)230-134(90-140(193)248)171(276)212-114(147(194)252)39-19-26-71-183)231-177(282)144(98(7)8)236-149(254)101(12)208-148(253)100(11)210-166(271)129(84-96(3)4)225-169(274)132(88-107-54-62-111(244)63-55-107)228-159(264)118(43-23-30-75-187)214-157(262)119(44-24-31-76-188)223-175(280)143(97(5)6)235-150(255)102(13)209-153(258)127(70-82-284-15)222-164(269)126(67-69-139(192)247)221-155(260)116(41-21-28-73-185)213-158(263)121(46-33-78-203-179(195)196)218-168(273)131(87-106-52-60-110(243)61-53-106)227-162(267)123(48-35-80-205-181(199)200)219-173(278)136(93-239)233-170(275)133(89-108-56-64-112(245)65-57-108)229-174(279)137(94-240)234-172(277)135(91-142(250)251)232-178(283)146(103(14)241)238-151(256)113(190)85-104-37-17-16-18-38-104/h16-18,37-38,50-65,95-103,113-137,143-146,239-245H,19-36,39-49,66-94,183-190H2,1-15H3,(H2,191,246)(H2,192,247)(H2,193,248)(H2,194,252)(H,207,257)(H,208,253)(H,209,258)(H,210,271)(H,211,249)(H,212,276)(H,213,263)(H,214,262)(H,215,259)(H,216,268)(H,217,272)(H,218,273)(H,219,278)(H,220,261)(H,221,260)(H,222,269)(H,223,280)(H,224,281)(H,225,274)(H,226,266)(H,227,267)(H,228,264)(H,229,279)(H,230,265)(H,231,282)(H,232,283)(H,233,275)(H,234,277)(H,235,255)(H,236,254)(H,237,270)(H,238,256)(H,250,251)(H4,195,196,203)(H4,197,198,204)(H4,199,200,205)(H4,201,202,206)/t100-,101-,102-,103+,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,143-,144-,145-,146-/m0/s1
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| Chemical Name |
(3S)-4-[[(2S)-1-[[(2S)-1-[[(2S)-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)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-4-amino-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-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]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-[[(2S,3R)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-4-oxobutanoic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.2485 mL | 1.2423 mL | 2.4846 mL | |
| 5 mM | 0.0497 mL | 0.2485 mL | 0.4969 mL | |
| 10 mM | 0.0248 mL | 0.1242 mL | 0.2485 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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