SYNTHESIS AND BIOLOGICAL-ACTIVITY OF PEPTIDE HYDROXAMATE INHIBITORS OF DEGRADATION OF SUBSTANCE-P ANALOGS

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 NN-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-I-125-tyroSyl5]SP(5-11) ([(I-125)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-mu-M), Boc-Phe-Phe-Trp-NHOH (9, IC50 = 5-mu-M) and desamino-Tyr-Phe-Phe-Gly-NHOH (22, IC50 = 1.8-mu-M). A model describing the interaction of these compounds with the active site is proposed.