Engineering galanin analogues that discriminate between GalR1 and GalR2 receptor subtypes and exhibit anticonvulsant activity following systemic delivery.
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.
Robertson
Charles R
CR
Department of Medicinal Chemistry, College of Pharmacy, University of Utah, 421 WakaraWay, Salt Lake City, Utah 84108, USA.
Scholl
Erika Adkins
EA
Pruess
Timothy H
TH
Green
Brad R
BR
White
H Steve
HS
Bulaj
Grzegorz
G
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
D000927:Anticonvulsants; D008024:Ligands; D009842:Oligopeptides; D044091:Receptor, Galanin, Type 1; D044092:Receptor, Galanin, Type 2; D019004:Galanin; D002118:Calcium