Dehydro ketomethylene and ketomethylene analogs of substance P: synthesis and biological activity

Abstract

The synthesis of dehydro keto methylene and keto methylene analogues of substance P using classical peptide synthesis is described. The following analogues were prepared: [pGlu6,Gly9.psi.(COCH2)(RS)Leu10]SP6-11 (4) and [pGlu6,-(RS)Phe7 .psi.(COCH2)(RS)Phe8]SP6-11(8). The use of an improved deprotection scheme employing Meerwein''s reagent (ETOBF4) made possible the synthesis of the novel dehydro keto methylene analogue [pGlu6,(RS)Phe.psi.-(COCH2).DELTA.(E) Phe8]SP6-11 (26) and the tetrapeptide analogue [pGlu6,(RS)Phe8.psi.(COCH2)Gly9]SP6-9(-OMe) (23). Compound 4 was a weak agonist in provoking contractions of the guinea pig ileum. Compound 26 was a potent inhibitor of SP degradation in rat hypothalamus preparations, with an IC50 value of 1.8 .mu.M.