title: Cyclic analogs of galanin and neuropeptide Y by hydrocarbon stapling.
abstract: Hydrocarbon stapling is an effective strategy to stabilize the helical conformation of bioactive peptides. Here we describe application of stapling to anticonvulsant neuropeptides, galanin (GAL) and neuropeptide Y (NPY), that are implicated in modulating seizures in the brain. Dicarba bridges were rationally introduced into minimized analogs of GAL and NPY resulting in increased α-helical content, in vitro metabolic stability and n-octanol/water partitioning coefficient (logD). The stapled analogs retained agonist activities towards their respective receptors and suppressed seizures in a mouse model of epilepsy.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT 84108, USA. brad.green@utah.edu
authors.forename: Brad R
authors.initials: BR
authors.lastname: Green
authors.forename: Brian D
authors.initials: BD
authors.lastname: Klein
authors.forename: Hee-Kyoung
authors.initials: HK
authors.lastname: Lee
authors.forename: Misty D
authors.initials: MD
authors.lastname: Smith
authors.forename: H
authors.initials: H
authors.lastname: Steve White
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D003500:Cyclization; D004355:Drug Stability; D004827:Epilepsy / Q000188:drug therapy*; D019004:Galanin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D051381:Rats
chemical_list: D000927:Anticonvulsants; D009478:Neuropeptide Y; D019004:Galanin