Y2/Y4 SELECTIVE RECEPTOR AGONISTS FOR THERAPEUTIC INTERVENTIONS

摘要

Y receptor agonists which are selective for Y2 and Y4 receptors over the Y1 receptor are useful for treatment of, for example obesity, are (a) PP-fold peptides or PP-fold peptides mimics which have (i) a C-terminal Y receptor-recognition amino acid sequence represented by -X-Thr-Arg-X;-Arg-Tyr-C(=0)NRR; wherein Rand Rare independently hydrogen or C-Calkyl, X is Val, lle, Leu or Ala, and Xis Gln or Asn, or a conservatively substituted variant thereof in which Thr is replaced by His or Asn and/or Tyr is replaced by Trp or Phe ; and/or Arg is replaced by Lys, and (ii) an N-terminal Y receptor-recognition amino acid sequence represented by HN-X;-Pro-X- (Glu or Asp)- wherein Xis not present or is amino acid residue, and Xis Leu or Ser or conservative substitutions of Leu or Ser, or (b) the said comprise a C-terminal Y receptor-recognition amino acid sequence as defined in (i) above, said Y receptor-recognition sequence being fused to an amphiphilic amino acid sequence domain comprising at least one alpha helical turn adjacent the N-terminus of the said hexapeptide sequence, said turn being constrained in a helical configuration by a covalent intramolecular link, and optionally an N-terminal sequence which commences with a Y receptor-recognition amino acid sequence as defined in (ii) above.