From the Anti-Nociceptive Substance P Metabolite Substance P (1-7) to Small Peptidemimetics.

Substance P (SP) is associated with pain and inflammatory processes and is released from terminals of specific sensory nerves. This undecapeptide that mediates its effects through the neurokinin type 1 (NK1) receptor, is rapidly degraded in vivo to smaller fragments. The heptapeptide SP(1-7) with a hitherto unknown receptor, is a major bioactive fragment and displays often opposite actions to those induced by SP. Hence, SP(1-7) elicits anti-nociceptive and anti-hyperalgesic effects. These observations have attracted a substantial interest and in this mini-review the efforts to transform the heptapeptide SP(1-7) into more drug-like small-molecule SP(1-7) peptidomimetics as a potential new class of analgesics are summarized. Structure-activity relationship studies and subsequent amidation of the C-terminal and truncations from the N-terminal of the heptapeptide delivered the bioactive dipeptide amide Gln-Phe-NH2 showing a high affinity at the SP(1-7) binding site. Similarly, endomorphin-2, an endogenous opioid ligand containing a C-terminal carboxamide group, demonstrated a high affinity at the SP(1-7) binding site. Endomorphin-2 subjected to truncations yielded the potent dipeptide amide Phe-Phe-NH2. Structural optimization of the latter furnished more drug-like high affinity ligands and among those a constrained cis-3-phenylpyrrolidine derivative that after peripheral administration produced a significant anti-allodynic effect in a mouse SNI model of neuropathic pain. This SP(1-7) peptidomimetic was as effective as SP(1-7) in alleviating mechanical allodynia in mice. Although, additional structural modifications are needed to achieve compounds exhibiting high/fair bioavailability after oral administration, the examples presented herein demonstrate that the bioactive peptides SP(1-7) and endomorphin-2 can be converted into low molecular weight compounds that are able to mimic the in vivo actions of the heptapeptide SP(1-7).