TY - JOUR
T1 - Synthesis and biological activity of peptide hydroxamate inhibitors of degradation of substance P analogues
AU - Ewenson, A.
AU - Laufer, R.
AU - Frey, J.
AU - Chorev, M.
AU - Selinger, Z.
AU - Gilon, C.
PY - 1992
Y1 - 1992
N2 - 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.
AB - 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.
KW - active site of substance P degrading enzyme
KW - inhibitors
KW - peptide hydroxamic acids
KW - substance P
KW - substance P analogue proteolysis
KW - substance P degrading enzyme
UR - http://www.scopus.com/inward/record.url?scp=0026680458&partnerID=8YFLogxK
U2 - 10.1016/0223-5234(92)90001-H
DO - 10.1016/0223-5234(92)90001-H
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AN - SCOPUS:0026680458
SN - 0223-5234
VL - 27
SP - 179
EP - 186
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 3
ER -
