title: Analgesic neuropeptide W suppresses seizures in the brain revealed by rational repositioning and peptide engineering.
abstract: Anticonvulsant neuropeptides play an important role in controlling neuronal excitability that leads to pain or seizures. Based on overlapping inhibitory mechanisms, many anticonvulsant compounds have been found to exhibit both analgesic and antiepileptic activities. An analgesic neuropeptide W (NPW) targets recently deorphanized G-protein coupled receptors. Here, we tested the hypothesis that the analgesic activity of NPW may lead to the discovery of its antiepileptic properties. Indeed, direct administration of NPW into the brain potently reduced seizures in mice. To confirm this discovery, we rationally designed, synthesized, and characterized NPW analogues that exhibited anticonvulsant activities following systemic administration. Our results suggest that the combination of neuropeptide repositioning and engineering NPW analogues that penetrate the blood-brain barrier could provide new drug leads, not only for the treatment of epilepsy and pain but also for studying effects of this peptide on regulating feeding and energy metabolism coupled to leptin levels in the brain.
authors: Department of Medicinal Chemistry, University of Utah, Salt Lake City,Utah 84108, United States.
authors: Brad R
authors: BR
authors: Green
authors: Misty
authors: M
authors: Smith
authors: Karen L
authors: KL
authors: White
authors: H Steve
authors: HS
authors: White
authors: Grzegorz
authors: G
authors: Bulaj
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000494:pharmacology / Q000627:therapeutic use*; D015202:Protein Engineering / Q000379:methods*; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000700:Analgesics; D000927:Anticonvulsants; C467731:NPW protein, human; D009479:Neuropeptides