Synthesis and biological activity of tripeptide FR113680 analogues containing unconventional amino acids.

In order to further develop structure-ativity relationships and to get information about the biological active conformations we synthetized analogues tuipeptide to the FR 113680 [Ac-Thr-D-Trp(CHO)-)-PheNMeBzl; Ac: acethyl], in which the phenylalanine residue was replaced by unconventional amino acids [1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); (3aS, 7aS)-octahydroindole-2-carboxylic acid (Oic); (S,S,S)-2-azabiciclo[3.3.0] octane-3-carboxylic acid (Aoc); 3-(1'-naphthyl) alanine (Nap), pheny(glicine (Phg); thienylalanine (Thi)]. The biological activity off he peptides was performed on guinea pig ileum for neurokinin 1 (NK-1) and on rat colon for neurokinin 2 (NK-2). In particular, the replacement of the Phe(3) by the Oic (8(a)) gave an higher antagonist activity in both NK-1 and NK-2 receptors, but no improvement in selectivity with respect to reference tripeptide (FR113680). The compound (8(a)) represent the first example of highly potent peptides that do not contain an aromatic amino acid of the third position as had been previously considered essential.