K receptor opioid peptides

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

Inactive Publication Date: 2004-06-23
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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  • K receptor opioid peptides
  • K receptor opioid peptides
  • K receptor opioid peptides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] The peptide of the following general formula is correctly synthesized by the familiar peptide synthesis method: H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt. For example, first use classical solution chemistry to synthesize a tripeptide: (α-amino protecting group)-D-Phe-D-Phe-D-Nle (carboxy protecting group). For example, the tripeptide can be prepared as follows. Dissolve H-D-Nle-Ome in DMF and add N-ethylmorpholine (NEM) to adjust the pH. Then, this solution was mixed with a DMF solution containing NEM's Boc-protected D-Phe-OH. Add activator or coupling agent to the reaction mixture, such as hexafluorophosphate benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium (BOP) or N,N'-diisopropyl A mixture of carbodiimide (DIC) and N-hydroxybenzotriazole (HOBt). After the reaction is completed, the medium is evaporated to dryness, and then the product is appropriately purified and recrystallized. Then the Boc protecting group was removed with trifluoroacetic acid (TFA), and the dipeptide was ...

Embodiment 2

[0065] Table A

[0066] Peptides 2 to 15 are believed to have long-lasting anti-nociceptive activity.

Embodiment 3

[0068] Table B

[0069] Peptides 16 to 39 are believed to have long-lasting anti-nociceptive activity.

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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 mainly relates to synthetic opioid peptides, specifically to opioid peptides as highly selective κ receptor activators, and more specifically to activators that (a) do not penetrate into the brain, and (b) ) Has long-term anti-nociceptive activity in vivo. Background of the invention [0002] Kappa opioid receptors (KOR) exist 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 called kappa activators. [0003] It is known that activating KOR in the brain can produce analgesic effects. Based on this discovery, people tried 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). It has been confirmed in animals and humans tha...

Claims

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Application Information

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Patent Type & Authority Patents(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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