title: Generating orally active galanin analogues with analgesic activities.
abstract: The endogenous neuropeptide galanin has anticonvulsant and analgesic properties mediated by galanin receptors expressed in the central and peripheral nervous systems. Our previous work showed that by combining truncation of the galanin peptide with N- and C-terminal modifications afforded analogues that suppress seizures or pain upon intraperitoneal (i.p.) administration. To generate orally active galanin analogues, the previously reported lead compound Gal-B2 (NAX 5055) was redesigned by 1) central truncation, (2) introduction of D-amino acids, and 3) addition of backbone spacers. Analogue D-Gal(7-Ahp)-B2, containing 7-aminoheptanoic acid as a backbone spacer and an oligo-D-lysine motif at the C terminus, exhibits anticonvulsant and analgesic activity post-i.p. administration. Oral administration of D-Gal(7-Ahp)-B2 demonstrates analgesic activity with decreases in both acute and inflammatory pain in the mouse formalin model of pain at doses as low as 8 mg kg(-1) .
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84108, USA. charles.robertson@utah.edu
authors.forename: Charles R
authors.initials: CR
authors.lastname: Robertson
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pruess
authors.forename: Erin
authors.initials: E
authors.lastname: Grussendorf
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D019004:Galanin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009420:Nervous System / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D010455:Peptides; D019004:Galanin