Substance P and analogues: biological activity and degradation

A series of C-terminal partial sequences of Substance P, either free or blocked at the amino terminus, has been synthesized. The peptides were examined for their relative potencies as smooth muscle contracting agents and for their rates of degradation by rat brain synaptosomes. The C-terminal hexapeptide in both the free and blocked forms displays activity comparable to that of the longer C-terminal peptides as well as to that of the native undecapeptide. The blocked peptides, however, are much more stable than the corresponding free peptides. Among the free peptides Substance P is degraded virtually at the same rate as the C-terminal octapeptide but significantly more slowly than the C-terminal hexa- or heptapeptides. These patterns of inactivation together with the response to inhibition by various protease inhibitors indicate that both endopeptidase(s) are involved in the degradation of Substance P. Degradation of the Substance P molecule at Substance P synapses may occur in two steps, first by a specific endopeptidase splitting the molecule into an N-terminal tetrapeptide and a C-terminal heptapeptide, the latter being degraded in a second step by aminopeptidases.