Z-Ala-Gly-OH (BAT-006559)
* For research use only

Category
Others
Catalog number
BAT-006559
CAS number
3235-17-4
Molecular Formula
C13H16N2O5
Molecular Weight
280.28
Z-Ala-Gly-OH
Synonyms
Z-L-alanyl-L-glycine; N-Carbobenzoxy-L-Alanylgylcine; Z Ala Gly OH
Appearance
White powder
Purity
≥ 96% (HPLC)
Density
1.285g/cm3
Melting Point
104 °C
Boiling Point
578.5°C at 760 mmHg
Storage
Store at 2-8 °C
InChI
InChI=1S/C13H16N2O5/c1-9(12(18)14-7-11(16)17)15-13(19)20-8-10-5-3-2-4-6-10/h2-6,9H,7-8H2,1H3,(H,14,18)(H,15,19)(H,16,17)/t9-/m0/s1
InChI Key
RNBMQRYMCAVZPN-VIFPVBQESA-N
Canonical SMILES
CC(C(=O)NCC(=O)O)NC(=O)OCC1=CC=CC=C1
1.Factors that restrict intestinal cell permeation of cyclic prodrugs of an opioid peptide (DADLE): Part II. Role of metabolic enzymes in the intestinal mucosa.
Ouyang H1, Chen W, Andersen TE, Steffansen B, Borchardt RT. J Pharm Sci. 2009 Jan;98(1):349-61. doi: 10.1002/jps.21424.
The objective of this study was to determine the relative importance of metabolism by cytochrome P450 (CYP) enzymes versus efflux by P-glycoprotein (P-gp) in restricting the intestinal mucosal permeation of cyclic prodrugs (AOA-DADLE, CA-DADLE, OMCA-DADLE) of the opioid peptide DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH). AOA-DADLE, CA-DADLE, and OMCA-DADLE were shown to be rapidly metabolized by rat liver microsomes and human CYP-3A4 and to a lesser extent by esterases. Using an in situ perfused rat ileum model, ketoconazole, a CYP 3A inhibitor, was shown to have no effect (AOA-DADLE) or a slight enhancing effect (OMCA-DADLE, twofold; CA-DADLE, threefold) on their intestinal mucosal permeation. In contrast, inclusion of PSC-833, a P-gp inhibitor, in the perfusate significantly enhanced (7-16-fold) the permeation of the three cyclic prodrugs. Since PSC-833 was found to be a weak inhibitor of CYP 3A4 and to have no inhibitory effects on esterases, phenol sulfotransferases, and glucuronyltransferases, it is suggested PSC-833 enhances intestinal mucosal permeation of these cyclic prodrugs by inhibiting their polarized efflux and not by inhibiting their metabolism.
2.Effects of amino acid chirality and the chemical linker on the cell permeation characteristics of cyclic prodrugs of opioid peptides.
Liederer BM1, Fuchs T, Vander Velde D, Siahaan TJ, Borchardt RT. J Med Chem. 2006 Feb 23;49(4):1261-70.
Previously, our laboratory showed that the oxymethyl-modified coumarinic acid (OMCA) cyclic prodrug of the opioid peptide DADLE ([D-Ala2,D-Leu5]-Enk, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) exhibited low permeation across both the intestinal mucosa and the blood-brain barrier (BBB). This low cell permeation arose from its strong substrate activity for efflux transporters in these biological barriers. In an attempt to determine whether the chirality of the amino acid asymmetric centers could influence the solution structure of the cyclic prodrugs and thus their substrate activities for efflux transporters, we synthesized cyclic prodrugs of the opioid peptides H-Tyr-Ala-Gly-Phe-D-Leu-OH ([Ala2,D-Leu5]-Enk), H-Tyr-D-Ala-Gly-Phe-Leu-OH ([D-Ala2,Leu5]-Enk), and H-Tyr-Ala-Gly-Phe-Leu-OH ([Ala2,Leu5]-Enk). In an attempt to determine whether the chemical linker (OMCA) bestowed efflux substrate activity on the cyclic prodrugs, we synthesized capped linear derivatives (acetylated on the N-terminal and amidated on the C-terminal end) of [Ala2,D-Leu5]-Enk, [D-Ala2,Leu5]-Enk, and [Ala2,Leu5]-Enk.
3.A comparison of the effects of p-glycoprotein inhibitors on the blood-brain barrier permeation of cyclic prodrugs of an opioid peptide (DADLE).
Ouyang H1, Andersen TE, Chen W, Nofsinger R, Steffansen B, Borchardt RT. J Pharm Sci. 2009 Jun;98(6):2227-36. doi: 10.1002/jps.21585.
The objective of this study was to elucidate the role of P-glycoprotein (P-gp) in restricting the blood-brain barrier (BBB) permeation of cyclic prodrugs of the opioid peptide DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH). The BBB permeation characteristics of these prodrugs and DADLE were determined using an in situ perfused rat brain model and in vitro cell culture model (MDCK-MDR1 cells) of the BBB. The activities of P-gp in these models were characterized using a known substrate (quinidine) and known inhibitors [cyclosporine A (CyA), GF-120918, PSC-833] of P-gp. Cyclic peptide prodrugs exhibited very poor permeation in both models. Inclusion of GF-120918, CyA, or PSC-833 in the brain perfusion medium or the cell culture medium significantly increased the permeation of these cyclic prodrugs. The order of potency of these P-gp inhibitors, as measured using the cyclic prodrugs as substrates, was, by in vitro MDCK-MDR1 cells: GF-120918 = CyA >or= PSC-833; and by in situ rat brain perfusion: GF-120918 > CyA = PSC-833.
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