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-XSUP3/SUP-Arg-Tyr-C(=0)NRSUP1/SUPRSUP2 /SUPwherein RSUP1 /SUPand RSUP1 /SUPare independently hydrogen or CSUB1/SUB-CSUB6 /SUBalkyl X is Val, Ile, Leu or Ala, and XSUP3 /SUPis 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 HSUB2/SUBN-XSUP1/SUP-Pro-XSUP2/SUP-(Glu or Asp)-wherein XSUP1 /SUPis not present or is amino acid residue, and XSUP2 /SUPis 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.