title: Engineering galanin analogues that discriminate between GalR1 and GalR2 receptor subtypes and exhibit anticonvulsant activity following systemic delivery.
abstract: Galanin modulates seizures in the brain through two galanin receptor subtypes, GalR1 and GalR2. To generate systemically active galanin receptor ligands that discriminate between GalR1 and GalR2, the GalR1-preferring analogue Gal-B2 (or NAX 5055) was rationally redesigned to yield GalR2-preferring analogues. Systematic truncations of the N-terminal backbone led to [N-Me,des-Sar]Gal-B2, containing N-methyltryptophan. This analogue exhibited 18-fold preference in binding toward GalR2, maintained agonist activity, and exhibited potent anticonvulsant activity in mice following intraperitoneal administration.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, 421 WakaraWay, Salt Lake City, Utah 84108, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Robertson
authors.forename: Erika Adkins
authors.initials: EA
authors.lastname: Scholl
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pruess
authors.forename: Brad R
authors.initials: BR
authors.lastname: Green
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D019004:Galanin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044091:Receptor, Galanin, Type 1 / Q000819:agonists / Q000378:metabolism*; D044092:Receptor, Galanin, Type 2 / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D008024:Ligands; D009842:Oligopeptides; D044091:Receptor, Galanin, Type 1; D044092:Receptor, Galanin, Type 2; D019004:Galanin; D002118:Calcium