Substance P analogues act as broad-spectrum neuropeptide antagonists

Neuropeptides including bombesin, vasopressin and bradykinin are increasingly implicated in the control of cell proliferation. There is now considerable evidence that the growth of certain common cancers including small cell lung cancer (SCLC) can be stimulated by multiple neuropeptides which act in an autocrine/paracrine fashion. Consequently, the development of broad spectrum neuropeptide antagonists could be of therapeutic interest. Indeed, certain substance P (SP) analogues including (DArg1, DPhe5, DTrp7,9, Leu11)SP and (Arg6, DTrp7,9, MePhe8)SP (6–11) inhibit the actions of multiple neuropeptides and block the growth of SCLC cells in vitro and in vivo. Moreover, one of these compounds is now in a phase I clinical study and so an understanding of the mechanism of action of these SP analogues is both of fundamental as well as clinical interest. We have found that the SP analogues coordinately and reversibly inhibit the downstream signals which emanate from neuropeptide receptors and competitively block the binding of neuropeptides to their respective receptors. These and other results using novel SP analogues which are reviewed here, suggest that the SP analogues act directly on the neuropeptide receptors to block neuropeptide action.