Synthesis and biological activity of peptide hydroxamate inhibitors of degradation of substance P analogues

A series of hydroxamic acid derivatives of peptides related to fragments of substance P (SP) were synthesized. Methyl, ethyl or N-hydroxy-succinimide ester precursors of the desired peptides were prepared by using classical peptide synthesis methodology and these were reacted with excess hydroxylamine in either ethanol or N,N-dimethylformamide. The products were characterized by chromatographic methods, amino acid analysis and fast atom bombardment mass spectrometry. The inhibition of the degradation of the radiolabelled substrate desamino-[3-¹²⁵I-tyrosyl⁵]SP(5-11) ([(¹²⁵I)BH⁵]SP(5-11)) by these compounds in rat hypothalamus preparations was determined. The most potent inhibitors found were Boc-Phe-Phe-Phe-NHOH (12d, IC₅₀ = 4 μM), Boc-Phe-Phe-Trp-NHOH (9, IC₅₀ = 5 μM) and desamino-Tyr-Phe-Phe-Gly-NHOH (22, IC₅₀ = 1.8 μM). A model describing the interaction of these compounds with the active site is proposed.