title: Small constrained SP1-7 analogs bind to a unique site and promote anti-allodynic effects following systemic injection in mice.
abstract: Previous results have shown that the substance P (SP) N-terminal fragment SP1-7 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 SP1-7. 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 SP1-7 target has yet been performed we screened our lead compound H-Phe-Phe-NH2 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 SP1-7, 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-NH2 analog, was shown to exhibit a significant anti-allodynic effect.
authors: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden. Electronic address: anna.jonsson@farmbio.uu.se.
authors: A
authors: A
authors: Jonsson
authors: Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: rebecca.fransson@orgfarm.uu.se.
authors: R
authors: R
authors: Fransson
authors: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden. Electronic address: y-harama@leh.kagoshima-u.ac.jp.
authors: Y
authors: Y
authors: Haramaki
authors: Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: anna.skogh@orgfarm.uu.se.
authors: A
authors: A
authors: Skogh
authors: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden. Electronic address: Erika.brolin@farmbio.uu.se.
authors: E
authors: E
authors: Brolin
authors: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden. Electronic address: hiroyuki.watanabe@farmbio.uu.se.
authors: H
authors: H
authors: Watanabe
authors: AstraZeneca, CNSP iMed Södertälje, Research & Development Innovative Medicines, SE-151 85 Södertälje, Sweden. Electronic address: gunnar.nordvall@gmail.com.
authors: G
authors: G
authors: Nordvall
authors: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden. Electronic address: mathias.hallberg@farmbio.uu.se.
authors: M
authors: M
authors: Hallberg
authors: Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: anja.sandstrom@orgfarm.uu.se.
authors: A
authors: A
authors: Sandström
authors: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden. Electronic address: fred.nyberg@farmbio.uu.se.
authors: F
authors: F
authors: Nyberg
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D019540:Area Under Curve; D001665:Binding Sites / Q000187:drug effects; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry* / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D018709:Statistics, Nonparametric; D013373:Substance P / Q000737:chemistry* / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D000700:Analgesics; D010446:Peptide Fragments; D013373:Substance P; C036877:substance P (1-7)
keywords: SP(1–7); anti-allodynia; peptidomimetics; receptor screening; spared nerve injury; substance P (SP)