Conjugates of neurotensin or neurotensin analogs and uses thereof

a neurotensin and analog technology, applied in the field of conjugates of neurotensin or neurotensin analogs and uses thereof, can solve the problems of delayed onset of hypothermia, difficulty in sustained maintenance of hypothermia, complex and expensive methods, etc., and achieve the effect of reducing the frequency or severity

Active Publication Date: 2010-10-07
ANGLACHEM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034]By “treating prophylactically” a disease, disorder, or condition in a subject is meant reducing the frequency of occurrence or severity of (e.g., preve...

Problems solved by technology

These techniques can be complex and expensive, and can lead to delays in the onset of hypothermia.
Sustained maintenance of hypothermia may also be difficult using these methods.
Finally, these methods can cause severe shivering, necessitating the need for co-medications such as paralytic agents or sedatives.
In the development of a new therapy for brain pathologies, the BBB is considered a major obstacle for the potential use of drugs fo...

Method used

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  • Conjugates of neurotensin or neurotensin analogs and uses thereof
  • Conjugates of neurotensin or neurotensin analogs and uses thereof
  • Conjugates of neurotensin or neurotensin analogs and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of a neurotensin-Angiopep-2 conjugate

[0145]An exemplary neurotensin-Angiopep-2 conjugate was synthesized using the scheme described below. As used in these examples, the abbreviation NT refers to the pE-substituted neurotensin peptide described below.

[0146]Neurotensin Peptide Synthesis

[0147]pELYENKPRRPYIL-OH, where the unusual amino acid L-pyroglutamic acid (pE) is used, was synthesized using SPPS (Solid phase peptide synthesis). SPPS was carried out on a Protein Technologies, Inc. Symphony® peptide synthesizer using Fmoc (9-fluorenylmethyloxycarbonyl) amino-terminus protection. The peptide was synthesized on a 100 μmol scale using a 5-fold excess of Fmoc-amino acids (200 mM) relative to the resin. Coupling was performed by a pre-loaded Fmoc-Leu-Wang resin (0.48 mmol / g) for carboxyl-terminus acids using 1:1:2 amino acid / activator / NMM in DMF with HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) and NMM (N-methylmorpholine). Deprotection was car...

example 2

Characterization of the NT-AN2Cys-NH2 conjugate

[0159]To investigate the pharmacological efficacy and brain penetration of the NT-AN2Cys-NH2 (NT-An2) conjugate, we monitored its effect on the body temperature of mice (FIG. 5). The temperature of mice was unaffected by intravenous administration of 1 mg / kg NT or the saline control. By contrast, intravenous administration of an equivalent dose of the conjugate (2.5 mg / kg) resulted in a rapid decrease in the body temperature, leading to hypothermia. The injection of a higher dose (5 mg / kg) of NT-An2 caused a stronger decrease in body temperature indicating that the effect of NT-An2 is dose dependent.

[0160]We also tested whether higher doses of the conjugate would results in greater induction of hypothermia. Mice were administered 5, 15, or 20 mg / kg of the conjugate, and the reduction in body temperature following administration was monitored for 120 minutes following administration. Small differences between these higher doses were obse...

example 3

Induction of Sustained Hypothermia Using Angiopep-NT Conjugates

[0163]We performed an additional experiments to test whether the conjugates were able to induce sustained hypothermia in mice and rats.

[0164]In a first experiment, mice first received an intravenous 5 mg / kg bolus injection of NT-An2, followed by an intravenous infusion (10 mg / kg / hr) 1 hour later for a duration of 2.5 hours. The body temperature continued to decrease during the infusion, reaching a nadir of −11° C. (FIG. 10). After the end of the infusion, body temperature slowly returned to 37° C., and the animals recovered.

[0165]A similar experiment was performed in rats. Here the rats were administered an intravenous bolus injection of 20 mg / kg NT-An2 immediately followed by a 20 mg / kg / hr infusion for 3.5 hours. This resulted in a maximal temperature drop of about 3.5° C. after 90 minutes (FIG. 11).

[0166]Sustained hypothermia experiments were performed using a intravenous bolus injection of 20 mg / kg of NT-An2 immediate...

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Abstract

The present invention features a compound having the formula A-X—B, where A is peptide vector capable of enhancing transport of the compound across the blood-brain barrier or into particular cell types, X is a linker, and B is a peptide therapeutic selected from the group consisting of neurotensin, a neurotensin analog, or a neurotensin receptor agonist. The compounds of the invention can be used to treat any disease in which increased neurotensin activity is useful and can be used to induce hypothermia or analgesia.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application Nos. 61 / 225,486, filed Jul. 14, 2009; 61 / 181,144, filed May 26, 2009; and 61 / 200,947, filed Dec. 5, 2008, each of which is hereby incorporated by reference.BACKGROUND OF THE INVENTION[0002]The invention relates to compounds including neurotensin, a neurotensin analog, or a neurotensin receptor agonist bound to a peptide vector and uses thereof. Neurotensin is 13 amino acid peptide possessing numerous biological activities. Injections of neurotensin in the central nervous system produce, among other effects, antipsychotic and hypothermic effects. Intravenous delivery of neurotensin, however, does not result in these effects, as the blood-brain barrier (BBB) effectively prevents peripheral neurotensin from reaching the receptors in the central nervous system (CNS) receptors.[0003]Reduction of body temperature (hypothermia) provides one of the best forms of neuroprotection a...

Claims

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Application Information

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IPC IPC(8): A61K38/10C07K7/02C07H21/04C12N15/63A61P23/00A61P25/18A61P25/34A61P25/36A61P25/30A61P25/32A61P3/10A61P3/04A61P3/06A61P9/12C12P21/02
CPCA61K38/00A61K47/48246C07K2319/03C07K14/8117C07K7/083A61K47/64A61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P9/12A61P17/02A61P23/00A61P25/00A61P25/18A61P25/30A61P25/32A61P25/34A61P25/36A61P29/00
Inventor CASTAIGNE, JEAN-PAULDEMEULE, MICHELCHE, CHRISTIANTHIOT, CARINEGAGNON, CATHERINE
Owner ANGLACHEM INC
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