Structure‐activity relationships of sialogogic heptapeptides analogous to physalaemin

Abstract

OBJECTIVES: The rationale behind this study was to determine in detail which amino acids in physalaemin are crucial to its sialogogue activity, with a view of synthesizing new sialogogues which might be of use in the treatment of dry mouth. METHODS: With the progressive elimination of amino acids, one by one, from the C‐ and N‐terminal regions, 126 heptapeptides were newly synthesized by the multi‐pin peptide method, for comparison with 11 naturally occurring tachykinins. RESULTS: The C‐terminal amide in position 11 was essential for salivation, but not the pyrolidine group or the N‐terminal amino acid residues in positions 1 to 4. In 18 heptapeptides in which M in position 11 (M11) was replaced by another amino acid, one by one, none caused salivation. In 18 heptapeptides, in which L10 or G9 was replaced, three peptides caused salivation but none had significantly increased secretory activities. In 18 hepta‐peptides in which Y8 was replaced, four caused salivation but only one (I) had significantly increased secretory activity. In 18 heptapeptides in which F7 was replaced, only Y caused salivation but with significantly reduced secretory activity. In contrast, in 18 heptapeptides in which K6 and N5 were replaced, most caused salivation and some of them had significantly increased secretory activities. CONCLUSIONS: It is concluded that the sequence FYGLM‐NH2 conserved in the C‐terminal region of phys‐alaemin is optimal, that amides in position 11 and F7 are very important for salivation, but that K6 and N5 can be replaced by some other amino acids, resulting in increased secretory activities.