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1. A calcitonin gene-related peptide (CGRP) agonist having the structure of Formula I:
X1—Y1—Z1 (I) wherein: X1 is an N-terminal fragment comprising at least about five to about seven amino acid residues having the general formula:(SEQ ID NO: 6)X1 X2 X3 Thr X4 Thr Cys wherein X1 is Ala or Cys or is not present, X2 is Cys, Ser or Gly, provided however that at least one of X1 and X2 is Cys and only one of X1 or X2 is Cys, X3 is Asp or Asn and X4 is Ala or Ser and wherein the terminal Cys of X1 is capable of forming a disulfide bridge with the Cys residue in X1 or X2;
Y1 is a central core comprising at least about 12 to about 24 and preferably about 15 amino acid residues wherein at least some of the residues of the central core are capable of forming an α-helix under physiological conditions, said central core having the general formula:
X5 Leu Gly Arg X6 X7 Gln X8 X9 X10 Arg X11 X12 Thr X13 (SEQ ID NO: 7)wherein X5 is Val or Met, X6 is Leu or Tyr, X7 is Ser or Thr, X8 is Asp or Glu, X9 is Phe or Leu, X10 is His or Asn, X11 is Phe or Leu, X12 is His or Gln, X13 is Phe or Tyr;
and Z1 is a C-terminal fragment comprising at least about six to about twelve amino acid residues, preferably about ten amino acid residues, said C-terminal fragment comprising a C-terminal amide, said fragment having the general formula:(SEQ ID NO: 8)Pro X14 Thr X15 Val Gly Ser Lys Ala Phe, wherein X14 is Arg or Gln and X15 is Asn or Ala;or pharmaceutically acceptable salt thereof, wherein said CGRP agonist has a higher binding affinity for human CGRP receptor than does human CGRP. |
