A quantitative structure-activity relationship study of some substance P-related peptides. A multivariate approach using PLS and variable selection.
Nine new analogues of substance P (SP) were designed using quantitative sequence-activity models based on the amino acid z-scales with PLS as the statistical method and the GOLPE procedure for variable selection. The nine SP analogues were synthesised by solid-phase peptide synthesis and tested for affinity to the NK-1 receptor from rat brain with radio receptor assay using [125I]-Bolton-Hunter substance P as labelled ligand. All of the new substance P analogues showed high affinities, with IC50 values of less than 0.8 nM. One analog, Lys-Arg-Ala-Lys-Phe-Met-Met-Phe-Phe-Gly-Leu-Let-NH2, showed a exceptional high affinity for the NK1 receptor, with IC50 = 5 pM.
Norinder
U
U
Astra Pain Control AB, Södertälje, Sweden.
Rivera
C
C
Undén
A
A
D000818:Animals; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D010455:Peptides; D018040:Receptors, Neurokinin-1; D013373:Substance P