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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Anticonvulsants / chemical synthesis*
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Anticonvulsants / chemistry
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Anticonvulsants / pharmacology
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Calcium / metabolism
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Galanin / analogs & derivatives*
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Galanin / chemical synthesis*
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Galanin / chemistry
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Galanin / pharmacology
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Humans
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In Vitro Techniques
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Ligands
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Mice
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Molecular Sequence Data
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Oligopeptides / chemical synthesis*
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Oligopeptides / chemistry
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Oligopeptides / pharmacology
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Radioligand Assay
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Rats
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Receptor, Galanin, Type 1 / agonists
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Receptor, Galanin, Type 1 / metabolism*
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Receptor, Galanin, Type 2 / agonists
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Receptor, Galanin, Type 2 / metabolism*
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Structure-Activity Relationship
Substances
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Anticonvulsants
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Ligands
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Oligopeptides
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Receptor, Galanin, Type 1
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Receptor, Galanin, Type 2
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Galanin
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Calcium