Abstract:The endogenous opioid peptide endomorphin-1 (1) was modified by attachment of lactose to the N-terminus via a succinamic acid spacer to produce compound 2. The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor binding affinity and agonist activity. Analogue 2 produced dose-dependent antinociceptive activity following intravenous administration in a chronic constriction injury (CCI) rat model of neuropathic pain with an ED(5… Show more
“…showing that the modification of opioid peptide endomorphin-1 by a lactose moiety resulted in significant analgesic activity of the peptide following oral administration to rats (Varamini et al, 2012). To the best of our knowledge, this is the first report of an orally administered LHRH analogue with a remarkable half-life and bioavailability.…”
Abstract:In the current study, the efficacy and pharmacokinetic profile of lactose-conjugated luteinizing hormone releasing hormone (LHRH) was examined following oral administration in male rats. A rapid and sensitive liquid chromatography/mass spectrometry technique was developed and applied for measuring the concentration of lactose[Q 1 ][w 6 ]LHRH (compound 1) in rat plasma in order to allow measurement of pharmacokinetic parameters. LH release was evaluated using a sandwich ELISA. Maximum serum concentration (Cmax= 0.11 µg/ml) was reached at 2 h (Tmax) following oral administration of the compound at 10 mg/kg. The half-life was determined to be 2.6 h. The absolute bioavailability of the orally administered compound was found to be 14%, which was a remarkable improvement compared to zero-tolow oral bioavailability of the native peptide. Compound 1 was effective in stimulating LH release at 20 mg/kg after oral administration. The method was validated at a linear range of 0.01-20.0 µg/ml and a correlation coefficient of r 2 ≥0.999. The accuracy and precision values showed the reliability and reproducibility of the method for evaluation of the pharmacokinetic parameters. These findings showed that the lactose derivative of LHRH has a therapeutic potential to be further developed as an orally active therapeutics for the treatment of hormone-dependent diseases.
“…showing that the modification of opioid peptide endomorphin-1 by a lactose moiety resulted in significant analgesic activity of the peptide following oral administration to rats (Varamini et al, 2012). To the best of our knowledge, this is the first report of an orally administered LHRH analogue with a remarkable half-life and bioavailability.…”
Abstract:In the current study, the efficacy and pharmacokinetic profile of lactose-conjugated luteinizing hormone releasing hormone (LHRH) was examined following oral administration in male rats. A rapid and sensitive liquid chromatography/mass spectrometry technique was developed and applied for measuring the concentration of lactose[Q 1 ][w 6 ]LHRH (compound 1) in rat plasma in order to allow measurement of pharmacokinetic parameters. LH release was evaluated using a sandwich ELISA. Maximum serum concentration (Cmax= 0.11 µg/ml) was reached at 2 h (Tmax) following oral administration of the compound at 10 mg/kg. The half-life was determined to be 2.6 h. The absolute bioavailability of the orally administered compound was found to be 14%, which was a remarkable improvement compared to zero-tolow oral bioavailability of the native peptide. Compound 1 was effective in stimulating LH release at 20 mg/kg after oral administration. The method was validated at a linear range of 0.01-20.0 µg/ml and a correlation coefficient of r 2 ≥0.999. The accuracy and precision values showed the reliability and reproducibility of the method for evaluation of the pharmacokinetic parameters. These findings showed that the lactose derivative of LHRH has a therapeutic potential to be further developed as an orally active therapeutics for the treatment of hormone-dependent diseases.
“…Acetylated, butanoic acid-conjugated carbohydrates were synthesized adapting or following published procedures (Varamini et al, 2012b) as summarized in Scheme 1, and 1 H-NMR spectra matched the published ones (Moradi et al, 2013). Chemical structures are shown in Table 1.…”
Section: Carbohydrate Synthesismentioning
confidence: 99%
“…Peptide analogs with a higher apparent permeability are shown to have better absorption and produce higher plasma peak concentrations compared to those with lower membrane permeability (Varamini et al, 2012b). A Caco-2 cell membrane model was used as a preliminary tool to screen membrane permeability.…”
Section: Caco-2 Cell Homogenate Stability and Membrane Permeability Amentioning
confidence: 99%
“…It caused an unprecedented 700-fold increase in membrane permeability of a different peptide (Varamini et al, 2012b).…”
Section: Caco-2 Cell Homogenate Stability and Membrane Permeability Amentioning
confidence: 99%
“…Conjugation to carbohydrates has been shown to considerably enhance peptide stability, permeation across biological membranes, and bioavailability (Egleton and Davis, 2005;Varamini et al, 2012b). Lipidation increases the lipophilicity and membrane-like properties of the peptides, thus facilitates their penetration across biological barriers (Griffin, 2011).…”
Graphical abstractGonadotropin-releasing hormone (GnRH) is an endogenous peptide with a short biological half-life. Although GnRH analogs (eg. triptorelin) are developed with enhanced stability compared to the native peptide, they still suffer from poor biological stability and pharmacokinetic properties. Furthermore, they are only effective in the treatment of hormone-dependent reproductive cancers. In this study we applied lipidation and glycosylation along with D-amino acid substitution at position 6 (D-Trp 6 ) to improve the stability, permeability, and consequently the potency of the GnRH peptide and triptorelin. We showed that the conjugation of GnRH with a lipid moiety and carbohydrates made all modified constructs (1-8) more stable than the parent peptide against enzymatic degradation (5.5 to 6.5 times). Two of the lactose-modified glycolipopeptides, 3 and 6, showed 27 and 16 times higher membrane permeability than the parent GnRH, respectively. All analogs with D-Trp 6 -substitution (4-6) exerted GnRH receptor-mediated antiproliferative activity in prostate and ovarian GnRH-receptor positive cell lines. They were more potent than triptorelin in the hormone-independent prostate cancer cell line: DU145. Compound 6 (lactose-modified) was the most potent analog for stimulating the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) gonadotropins from rat pituitary cells in vitro. The same glycolipopeptide exhibited a higher efficacy and duration of action in stimulating the release of LH than triptorelin in a preclinical mouse model. The superior activity 2 of lipid-and carbohydrate-substituted triptorelin analog 6 made it a promising candidate for the development of new GnRH agonists to treat both hormone-dependent and hormone-refractory prostate cancer..LIST OF ABBREVIATIONS
We report a strategy for stereoselective O‐aryl‐glycoside synthesis by copper‐catalyzed cross‐coupling of a variety of anomeric sugars and (hetero)aromatic iodides. Stereocontrol of the α/β selectivity can be successfully realized by slight structural modifications of the oxalic diamide ligands. Mechanistic studies indicated a dynamic kinetic resolution (DKR) reaction mechanism controlled by the ligand structures. This reaction could be performed on gram scale, and has also been applied to the synthesis of some natural products.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.