title: Design, synthesis, and characterization of high-affinity, systemically-active galanin analogues with potent anticonvulsant activities.
abstract: Galanin is an endogenous neuropeptide that modulates seizures in the brain. Because this neuropeptide does not penetrate the blood-brain barrier, we designed truncated galanin analogues in which nonessential amino acid residues were replaced by cationic and/or lipoamino acid residues. The analogues prevented seizures in the 6 Hz mouse model of epilepsy following intraperitoneal administration. The most active analogue, Gal-B2 (NAX 5055), contained the -Lys-Lys-Lys(palmitoyl)-Lys-NH(2) motif and exhibited high affinity for galanin receptors (K(i) = 3.5 nM and 51.5 nM for GalR1 and GalR2, respectively), logD = 1.24, minimal helical conformation and improved metabolic stability. Structure-activity-relationship analysis suggested that cationization combined with position-specific lipidization was critical for improving the systemic activity of the analogues. Because the anticonvulsant activity of galanin is mediated by the receptors located in hippocampus and other limbic brain structures, our data suggest that these analogues penetrate into the brain. Gal-B2 may lead to development of first-in-class antiepileptic drugs.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah 84108, USA. bulaj@pharm.utah.edu
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
authors.forename: Brad R
authors.initials: BR
authors.lastname: Green
authors.forename: Hee-Kyoung
authors.initials: HK
authors.lastname: Lee
authors.forename: Charles R
authors.initials: CR
authors.lastname: Robertson
authors.forename: Karen
authors.initials: K
authors.lastname: White
authors.forename: Liuyin
authors.initials: L
authors.lastname: Zhang
authors.forename: Marianna
authors.initials: M
authors.lastname: Sochanska
authors.forename: Sean P
authors.initials: SP
authors.lastname: Flynn
authors.forename: Erika Adkins
authors.initials: EA
authors.lastname: Scholl
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pruess
authors.forename: Misty D
authors.initials: MD
authors.lastname: Smith
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004827:Epilepsy / Q000188:drug therapy*; D019004:Galanin / Q000031:analogs & derivatives* / Q000737:chemistry*; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D008968:Molecular Conformation
chemical_list: D000927:Anticonvulsants; D008024:Ligands; D019004:Galanin