TH65056A - Opioid peptides for kappa receptors - Google Patents

Abstract

DC60 (01/09/52) A peptide that exhibits high local activity for the kappa opioid receptor (KOR) and has a time period of... Long-acting peripheral neuroprotective agents without cerebral infiltration have been developed, which are the amino acid sequences of either C-terminated D-isomers (meaning unilateral or bilaterally substituent amides). Representative compounds, which have KOR compatibility at least 1,0C0 times that of their muopioid receptor compatibility and an ED50 value no greater than 0.5 mg/kg, include H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt, H-D-Phe-D-Phe-D-Nle-D-Arg-morpholinil, H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-picolil, H-D-Phe-D-Phe-D-Nle-D-Arg-NHPr, and H-D-Phe-D-Phe-D-Nle-D-Arg-thiomorpholinil. 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-morpholinil, H-D-4Fpa-D-Phe-D-Nle-D-Arg-NH-4-picolil, H-D-Phe-D-Phe-D-Nle-D-Arg-NH-cyclopropyl, H-D-Ala (2Thi)-D-3, 4-Cpa-D-Leu-D-Arg-morpholinil, H-D-Phe-D-Phe-D-Nle-D-Gmf-morpholinil, H-D-Phe-D-Phe-D-Leu-D-Orn-NH (Aeb), H-D-Phe-D-Phe-D-Leu-D-Leu-D-Lys-morpholinil, H-D-Phe-D-Phe-D-Nle-D-Arg-piperazinil, and H-D-Phe-D-Phe-D-Nle-D-Arg-NH(Hoh). Peptides exhibiting high specific activity for kappa opioid receptors (KOR) and exhibiting a long peripheral neuronal duration without cerebral infiltration were developed. These are sequences of the amino acid rests of either the C-terminal D-isomer, meaning either a single or double-substantiated amide. Representative compounds exhibiting compatibility with kappa opioid receptors and having an ED50 of no more than 0.5 mg/kg include (chemical formulas).

Claims (1)

1. Opioid peptides, synthetic amides, or pharmaceutically acceptable salts of this substance, exhibiting at least 1000 times greater compatibility with the opioid mu opioid receptor and demonstrating a long duration of action when used in cells. The peptide has the formula: H-Xaa1-Xaa2-Xaa3-Xaa4-Q, or is a diamino-linked dimer of this substance, such as 1,6-diaminohexane, 1,5-diamino-3-oxapentane, and 1,8-diamino-3,6-dioxaoctane; Xaa is (A) D-Phe,(CalphaMe)D-Phe,D-Tyr,D-Tic or D-Ala (cyclopentyl or thienyl), where A is H,NO2,F,C1 or CH3; Xaa2 is (A') D-Phe,D-1Nal,D-2Nal, D-Tyr or D-Trp, where A' is A or 3,4C12,4Br or 2,4C12; Xaa3 is D-Nle,(B) D-Leu,D-Hal,D-Met, D-Val, D-Phe or D-Ala (cyclopentyl), where B is H or CalphaMe; Xaa4 is D-Arg,D-Har, D-nArg,D-Lys, D-I1y, D-Arg(Et2),D-Har(Et2), D-Amf, D-Gmf, D-Dbu, D-Orn, D-Ior, D-Lys (Bu) or D-Lys (Et2) and Q is NR1R2, morpholinyl, thiomorpholinyl, (C) piperidinyl, piperazinyl, 4-mono- or 4,4-di-piperazinyl with two substituents at position 4,4 or E-lysyl, where R1 is a C1 to C6 alkyl, a C1 to C6 alkyl with substituents, benzyl, benzyl with substituents, aminocyclohexyl, 2-thiazolyl, 2-picolyl, 4-picolyl, w-(acylmino)polymethylene or poly(oxyethylene), and where R2 is H or a C1 to C6 alkyl; And where C is H, 4-hydroxy or 4-oxo, where Tic is 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Amf is (NH2CH2)Phe, Gmf is Amf (amino) where Phe at position 4 is replaced by CH2NHC(NH)NH2, dBU is alpha,gamma-diaminobutyric acid, and Ior is isopropyl Orn where the amino chain is alkylated by isopropyl, or where the N end of the peptide is permethylated. (permethylated) 2. Synthetic peptides according to patent claim 1, where Xaa2 means D-Phe, Xaa3 means D-Leu or D-Nle, and Xaa4 means D-Arg or D-Om. 3. Synthetic peptides according to either patent claim 1 or 2, where Q means NHR1 and R1 means ethyl propyl butyl cyclopropyl or cyclobutyl. 4. Synthetic peptides according to either patent claim 1 or 2, where Q means morpholinyl or thiomerfolinyl. 5. Synthetic peptides according to either patent claim 1 or 2, where Q means NHR1 and R1 means 4-picolyl. 6. Synthetic peptides according to either patent claim 1 or 2, where Q means N(Et)2 NH(Aeb) Ppz or Pcp. 7. Synthetic peptides under either claim 1 or 2, where Q means NHR1 and R1 means Aao, Aoo, Hoh, Ghx, or Gao. 8. Synthetic peptides under any of claim 1-7, where Xaa1 means D-Phe, D-Ala(2-thianniyl), or D-4Fpa. 9. Synthetic peptides under claim 1, where Xaa4 means D-Gmf. 10. Synthetic peptides under claim 1, where Xaa2 means D-4Cpa or D-3,4Cpa. 11. Pharmaceutical mixtures containing an anti-symptom dose. 12. Synthetic peptides under patent claim 1, with a WT-ED50 of approximately 0.5 mg/kg or less, where the peptide has the formula (chemical formula). 13. Synthetic peptides under patent claim 12, where Xaa2 means D-Phe, D-4 Cpa or d-3, 4 Cpa, Xaa3 means D-Leu or D-Nle and Xaa4 means D-Arg, D-Om and D-Gmf. 14. Synthetic peptides under either claim 12 or 13, where Q means (formula) to claim 18. 19. Synthetic peptides under any of claim 12-18, where Xaa1 20. A synthetic peptide according to claim 1, having one of the following formulas (chemical formula). 21. An opioid peptide synthetic according to claim 1, having an ED50 of approximately 0.5 mg/kg or lower, with the chemical formula 22. (Chemical formula) (22 claims, 3 pages, 0 images)