title: Structural requirements for a lipoamino acid in modulating the anticonvulsant activities of systemically active galanin analogues.
abstract: Introduction of lipoamino acid (LAA), Lys-palmitoyl, and cationization into a series of galanin analogues yielded systemically active anticonvulsant compounds. To study the relationship between the LAA structure and anticonvulsant activity, orthogonally protected LAAs were synthesized in which the Lys side chain was coupled to fatty acids varying in length from C(8) to C(18) or was coupled to a monodispersed polyethylene glycol, PEG(4). Galanin receptor affinity, serum stability, lipophilicity (log D), and activity in the 6 Hz mouse model of epilepsy of each of the newly synthesized analogues were determined following systemic administration. The presence of various LAAs or Lys(MPEG(4)) did not affect the receptor binding properties of the modified peptides, but their anticonvulsant activities varied substantially and were generally correlated with their lipophilicity. Our results suggest that varying the length or polarity of the LAA residue adjacent to positively charged amino acid residues may effectively modulate the antiepileptic activity of the galanin analogues.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah, 84108, USA.
authors.forename: Liuyin
authors.initials: L
authors.lastname: Zhang
authors.forename: Charles R
authors.initials: CR
authors.lastname: Robertson
authors.forename: Brad R
authors.initials: BR
authors.lastname: Green
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pruess
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; D001667:Binding, Competitive; D002627:Chemistry, Physical; D002942:Circular Dichroism; D004827:Epilepsy / Q000188:drug therapy; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019004:Galanin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D051381:Rats; D044091:Receptor, Galanin, Type 1 / Q000378:metabolism; D044092:Receptor, Galanin, Type 2 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D005227:Fatty Acids; D044091:Receptor, Galanin, Type 1; D044092:Receptor, Galanin, Type 2; D019004:Galanin; D008239:Lysine