Ketomethylene pseudopeptide analogues of substance P: synthesis and biological activity

Two pseudopeptide analogues [Bz-(RS)Phe8 psi (COCH2)Gly9]SP8-11 (I) and [pGlu6,(RS)Phe8 psi (COCH2)Gly9]SP6-11 (II) of the substance P related C-terminal hexapeptide [pGlu6]SP6-11 were prepared as follows. The pseudodipeptidic unit H(RS)Phe psi (COCH2)GlyOH was synthesized by using a modified Dakin-West reaction between Bz-Phe-OH and monomethyl succinoyl chloride. The N alpha-protected pseudopeptidic unit was then incorporated into the appropriate peptide by using various coupling methods. The two pseudopeptide analogues were purified, characterized, and tested for their biological activity and inhibitory effect on SP degrading enzymes. Analogue II was a full agonist contracting the isolated guinea pig ileum with a potency of 70% compared to the parent hexapeptide [pGlu6]SP6-11. It was also a potent inhibitor of SP degrading activity in rat diencephalon membranes with a Ki of 20 microM whereas analogue I was a weak inhibitor.