Analogues of substance P containing an α-hydroxy, β-amino acid: synthesis and biological activity

Several bestatin-like analogues of pGlu⁶-Phe⁷-Phe⁸-Gly⁹-Leu¹⁰-Met¹¹-NH₂, a C-terminal hexapeptide derived from substance P (SP), an endogenous mammalian neuropeptide, were prepared. In this sequence [pGlu⁶]SP(6-11), Phe⁷ or Phe⁸ were substituted by the amino acid. (R,S)-α-hydroxy, (S)-β-amino, 4-phenylbutyric acid (AHPA). Several key diastereomeric products were resolved by selective precipitation from the reaction mixture and the resolved components were characterized by chromatography. FAB-mass spectrometry and amino acid analysis. The inhibitory potency of these peptides on SP degradation in rat diencephalon preparations was assayed. It was found that one of the resolved diastereomeric analogues, [pGlu⁶, AHPA⁸]SP(6-11) (9a) was a potent inhibitor of SP degradation with an IC₅₀ of 20 μM. The analogues prepared in this study were devoid of spasmogenic activity on the guinea-pig ileum assay.