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K receptor opioid peptides

A technology of opioid substances and receptors, applied in the field of synthetic opioid peptides, can solve problems such as polyuria

Inactive Publication Date: 2001-02-07
CARA THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the development of systemic kappa activators was discontinued because they were shown to also have certain side effects, such as polyuria, lethargy, and restlessness, which were mediated by kappa receptors in the brain

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Peptides of the general formula: H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt were correctly synthesized by familiar peptide synthesis methods. For example, the tripeptide is first synthesized by classical solution chemistry: (α-amino protecting group)-D-Phe-D-Phe-D-Nle (carboxyl protecting group). For example, the tripeptide can be prepared as follows. Dissolve H-D-Nle-Ome in DMF, and add N-ethylmorpholine (NEM) or the like to adjust the pH. This solution was then mixed with NEM-containing Boc-protected D-Phe-OH in DMF. To the reaction mixture is added an activator or coupling agent such as benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) or N,N'-diisopropyl A mixture of carbodiimide (DIC) and N-hydroxybenzotriazole (HOBt). After completion of the reaction, the medium is evaporated to dryness and the product is suitably purified and recrystallized. The Boc protecting group was then removed with trifluoroacetic acid (TFA), and the dipeptide was redi...

Embodiment 2

[0051] Table A

[0052] Peptides 2 to 15 are believed to have long-lasting antinociceptive activity.

Embodiment 3

[0054] Form B

[0055] Peptides 16 to 39 are believed to have long-lasting antinociceptive activity.

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PUM

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Abstract

Peptides which exhibit high selectivity for the kappa opioid receptor (KOR) and long duration of peripheral action without significant entry into the brain are created which are sequences of four D-isomer amino acid residues having a C-terminus which is a mono- or di-substituted amide. Representative compounds, which have an affinity for the KOR at least 1,000 times their affinity for the mu opioid receptor and an ED50 of not greater than about 0.5 mg / kg, include H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt, H-D-Phe-D-Phe-D-Nle-D-Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-picolyl, H-D-Phe-D-Phe-D-Nle-D-Arg-NHPr, H-D-Phe-D-Phe-D-Nle-D-Arg-thiomorpholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg-NEt2, H-D-Phe-D-Phe-D-Nle-D-Arg-NHMe, H-D-Phe-D-Phe-D-Leu-D-Orn-morpholinyl, H-D-4Fpa-D-Phe-D-Nle-D-Arg-NH-4-picolyl, H-D-Phe-D-Phe-D-Nle-D-Arg-NH-cyclopropyl, H-D-Ala-(2Thi)-D-3, 4Cpa-D-Leu-D-Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D-Gmf-morpholinyl, H-D-Phe-D-Phe-D-Leu-D-Orn-NH(Aeb), H-D-Phe-D-Phe-D-Leu-D-Lys-morpholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg-piperazinyl, and H-D-Phe-D-Phe-D-Nle-D-Arg-NH(Hoh).

Description

[0001] The present invention relates generally to synthetic opioid peptides, and in particular to opioid peptides that are highly selective κ receptor activators, and more particularly to activators that (a) do not penetrate the brain, and (b ) has long-term antinociceptive activity in vivo. Background of the invention [0002] The kappa opioid receptor (KOR) is present in the brain, spinal cord, central and peripheral nerve endings, (somatic and visceral) primary sensory afferent nerve cell bodies, and immune cells. Molecules that activate KOR are generally referred to as kappa activators. [0003] Activation of KOR in the brain is known to produce analgesic effects. Based on this finding, attempts were made to develop brain-permeable non-peptide κ activators as new analgesics to avoid the side effects (constipation, respiratory depression) of morphine analogs acting on the mu opioid receptor (MOR). , dependence and addiction). Such compounds have bee...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K38/07A61P1/04A61P13/00A61P13/10A61P25/04C07K5/10C07K5/107C07K5/117
CPCC07K5/1027C07K5/1016A61K38/00C07K5/1024A61P1/04A61P1/14A61P13/00A61P13/10A61P25/04A61P29/00A61P37/02
Inventor J·L·朱尼英P·J·M·里弗C·D·施泰英阿特J·S·迪亚斯J·A·特罗内尔T·W·范德阿
Owner CARA THERAPEUTICS
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