Small constrained SP 1-7 analogues bind to a unique site and promote anti-allodynic effects following systemic injection in mice

• Published in: Neuroscience 2015, Vol.298, p.112
• Main Authors: Jonsson, Anna, Fransson, Rebecca, Haramaki, Yutaka, Skogh, Anna, Brolin, Erika, Watanabe, Hiroyuki, Nordvall, Gunnar, Hallberg, Mathias, Sandström, Anja, Nyberg, Fred
• Format: Article
• Language: English
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2015.04.002

Previous results have shown that the substance P (SP) N-terminal fragment SP 1–7 may attenuate hyperalgesia and produce anti-allodynia in animals using various experimental models for neuropathic pain. The heptapeptide was found to induce its effects through binding to and activating specific sites apart from any known neurokinin or opioid receptor. Furthermore, we have applied a medicinal chemistry program to develop lead compounds mimicking the effect of SP 1–7 . The present study was designed to evaluate the pharmacological effect of these compounds using the mouse spared nerve injury (SNI) model of chronic neuropathic pain. Also, as no comprehensive screen with the aim to identify the SP 1–7 target has yet been performed we screened our lead compound H-Phe-Phe-NH 2 toward a panel of drug targets. The extensive target screen, including 111 targets, did not reveal any hit for the binding site among a number of known receptors or enzymes involved in pain modulation. Our animal studies confirmed that SP 1–7 , but also synthetic analogs thereof, possesses anti-allodynic effects in the mouse SNI model of neuropathic pain. One of the lead compounds, a constrained H-Phe-Phe-NH 2 analog, was shown to exhibit a significant anti-allodynic effect.