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.