Investigation of the importance of the N-terminal peptide bonds of substance P by synthetic pseudopeptide analogs.
Synthetic Substance P analogs where each of the first five peptide bonds are replaced by the peptide bond surrogate Gly psi [CH2CH2]Gly are investigated as ligands to the Neurokinin 1 (NK1) receptor from rat cerebral cortex. The affinities of these analogs are then compared with the corresponding Gly-Gly analogs. With this model system replacement of the peptide bond between position 4 and 5 with psi [CH2CH2] resulted in a 7-fold reduction of affinity. Substitution of other peptide bonds resulted in only minor changes in affinity. Although the N-terminal hexapeptide is important for high affinity binding to the NK1 receptor the present study provides evidence for that this effects is not caused by the side chains of the amino acids in position 1-6 or as results of intramolecular hydrogen bonding with the C-terminal part of the peptide. A possible exception is the peptide bond that in the native peptide connects Pro4 and Gln5.
Rivera Baeza
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Department of Biochemistry, Arrhenious Laboratory, Stockholm University, Sweden.
Undén
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D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D005998:Glycine / Q000737:chemistry; D008297:Male; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D018039:Receptors, Tachykinin; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism
D010455:Peptides; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D013373:Substance P; D005998:Glycine