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-X³-Arg-Tyr-C(=0)NR¹R² wherein R¹ and R¹ are independently hydrogen or C₁-C₆ alkyl X is Val, Ile, Leu or Ala, and X³ is 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 H₂N—X¹-Pro-X²—(Glu or Asp)—wherein X¹ is not present or is amino acid residue, and X² is 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.