Backbone-to-backbone cyclized and linear pseudopeptide analogs of substance P as ligands to the substance P receptor...

Two series of backbone modified substance P analogs were synthesized. In the first group of analogs the N-terminal region of substance P, SP(1-4), was replaced by a polyamine segment or aliphatic omega-amino fatty acid residues. Two of these analogs displaced 125I-Bolton-Hunter labeled substance P from rat brain synaptosomes with IC50 values of 1.3 +/- 0.5 and 1.6 +/- 0.3 nM, respectively. These affinities are similar to that of substance P (IC50 1.3 nM). The second group of analogs were a set of backbone-to-backbone cyclized pseudopeptides. In these analogs two peptide bonds at the C-terminal portion of substance P were replaced by the reduced peptide bonds (psi[CH2NH]) which were further reductively alkylated with 3(4-methylbenzylthio)propanal. After cleavage from the resin the peptides were oxidized into a cyclic disulfide. All of the cyclic analogs of substance P interacted with the NK1 receptor from rat brain with IC50 values in the micromolar range.