Receptor(SSTR4)-selective somatostatin analogs
First Claim
1. A cyclic somatostatin (SRIF) analog peptide which selectively binds the SRIF receptor SSTR4, which peptide comprises the amino acid sequence (cyclo)Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Phe-Xaa7-Xaa8-Lys-Thr-Xaa11-Xaa12-Xaa13-Cys (SEQ ID NO:
- 2) wherein Xaa1 is des-Xaa, D-Ala, Ala, L-Hor, Cbm, an acyl group having up to 20 carbon atoms or alkyl(C1 to C6);
Xaa2 is Tyr, D-Tyr, Gly or des-Xaa;
Xaa3 is Cys or D-Cys;
Xaa4 is Lys or des-Xaa;
Xaa5 is Asn or des-Xaa;
Xaa7 is an amino acid selected from the group consisting of Ala, Aph, Amp, Iamp, Val and Tyr;
Xaa8 is an amino acid selected from the group consisting of (A)Trp, (A)D-Trp, 2Nal and threo-L-Cβ
Me-2Nal, wherein A is H, Cl, F, Br, Me, NO3, OMe or formyl;
Xaa11 is Ala, Gly, Val, Phe or Tyr;
Xaa12 is Thr or des-Xaa; and
Xaa13 is Ser, D-Ser or des-Xaa;
provided that when Xaa7 is Tyr, Xaa8 is threo-L-Cβ
Me-2Nal.
2 Assignments
0 Petitions
Accused Products
Abstract
Analogs of SRIF which are selective for SSTR4 in contrast to the other cloned SRIF receptors are useful in determining tissue and cellular expression of the receptor SSTR4 and its biological role in regulating tumor growth. SRIF analog peptides, such as des-AA1,2,4,5,12,13[Ala7]-SRIF; des-AA1,2,4,5,12,13[Aph7]-SRIF, des-AA1,2,4,5,12,13[Aph7]Cbm-SRIF; des-AA1,2,4,5,12,13[Tyr2,Ala7]-Cbm-SRIF, and des-AA1,2,4,5,12,13[Tyr7,CβMe-L-2Nal8]-SRIF, and counterparts incorporating D-Cys3 and/or D-Trp8 and/or Ala11, bind with high affinity to the cloned human receptor SSTR4 and activate the receptor, but they do not bind with significant affinity to human SSTR1, SSTR2, SSTR3 or SSTR5. By incorporating an iodinated tyrosine in position-2 in these SSTR4-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. Alternatively, for use in therapy, cytotoxins or highly radioactive elements can be N-terminally coupled or complexed thereto.
43 Citations
20 Claims
-
1. A cyclic somatostatin (SRIF) analog peptide which selectively binds the SRIF receptor SSTR4, which peptide comprises the amino acid sequence (cyclo)Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Phe-Xaa7-Xaa8-Lys-Thr-Xaa11-Xaa12-Xaa13-Cys (SEQ ID NO:
- 2) wherein Xaa1 is des-Xaa, D-Ala, Ala, L-Hor, Cbm, an acyl group having up to 20 carbon atoms or alkyl(C1 to C6);
Xaa2 is Tyr, D-Tyr, Gly or des-Xaa;
Xaa3 is Cys or D-Cys;
Xaa4 is Lys or des-Xaa;
Xaa5 is Asn or des-Xaa;
Xaa7 is an amino acid selected from the group consisting of Ala, Aph, Amp, Iamp, Val and Tyr;
Xaa8 is an amino acid selected from the group consisting of (A)Trp, (A)D-Trp, 2Nal and threo-L-Cβ
Me-2Nal, wherein A is H, Cl, F, Br, Me, NO3, OMe or formyl;
Xaa11 is Ala, Gly, Val, Phe or Tyr;
Xaa12 is Thr or des-Xaa; and
Xaa13 is Ser, D-Ser or des-Xaa;
provided that when Xaa7 is Tyr, Xaa8 is threo-L-Cβ
Me-2Nal. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)
- 2) wherein Xaa1 is des-Xaa, D-Ala, Ala, L-Hor, Cbm, an acyl group having up to 20 carbon atoms or alkyl(C1 to C6);
-
18. A cyclic somatostatin (SRIF) analog peptide having specific affinity for the SRIF receptor SSTR4, which peptide has an amino acid sequence at least 8 residues in length, contains a Cys-Cys disulfide bond with a sequence of at least 6 residues located between said Cys residues as a ring, and contains Phe-Xaa7-Xaa8-Lys-Thr-Xaa11 (SEQ ID NO:
- 10) or its equivalent adjacent the Cys residue near the N-terminus, which analog peptide is characterized by the presence of Xaa7 in the form of Ala, Aph, Amp or lamp;
Xaa8 being (A)Trp, (A)D-Trp or 2Nal, wherein A is H, Cl or F and B is H, Cl, F or NO; and
Xaa11 being Ala, Phe or Tyr.
- 10) or its equivalent adjacent the Cys residue near the N-terminus, which analog peptide is characterized by the presence of Xaa7 in the form of Ala, Aph, Amp or lamp;
-
19. A method of identifying a ligand that is selective for the SRIF receptor SSTR4 which is patterned after the structure of the cyclic ligand SRIF, which method comprises:
-
providing a pharmacophore model embodying precise 3-dimensional characteristics wherein the distances (a) between the Cγ
of the side chain of residue 8 or its equivalent and the Cγ
of that of an aromatic residue is 5.5-9.5 Å
;
(b) between the Cγ
of said side chain of residue 8 or its equivalent and the Cγ
of the side chain of Lys9 or its equivalent is 4.5-6.5 Å
; and
(c) between the Cγ
of said side chain of said aromatic residue or its equivalent and the Cγ
of said side chain of Lys9 or its equivalent is 4.5-6.5 Å
, andusing said pharmacophore model and 3-D computer analysis to predict the construction of a ligand which binds selectively and with high affinity to SSTR4. - View Dependent Claims (20)
-
Specification