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Structural requirements for a lipoamino acid in modulating the anticonvulsant activities of systemically active galanin analogues.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 Mar 12; Vol. 52 (5), pp. 1310-6. - Publication Year :
- 2009
-
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.
- Subjects :
- Amino Acid Sequence
Animals
Anticonvulsants chemistry
Anticonvulsants pharmacology
Binding, Competitive
Chemistry, Physical
Circular Dichroism
Epilepsy drug therapy
Fatty Acids chemistry
Fatty Acids pharmacology
Galanin chemistry
Galanin pharmacology
Humans
Hydrophobic and Hydrophilic Interactions
In Vitro Techniques
Lysine chemistry
Lysine pharmacology
Mice
Molecular Sequence Data
Protein Structure, Secondary
Rats
Receptor, Galanin, Type 1 metabolism
Receptor, Galanin, Type 2 metabolism
Structure-Activity Relationship
Anticonvulsants chemical synthesis
Fatty Acids chemical synthesis
Galanin analogs & derivatives
Galanin chemical synthesis
Lysine analogs & derivatives
Lysine chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19199479
- Full Text :
- https://doi.org/10.1021/jm801397w