Optically Pure, Structural, and Fluorescent Analogues of a Dimeric Y4 Receptor Agonist Derived by an Olefin Metathesis Approach.
The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors and as a lead compound for antiobesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labeled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)-diaminosuberoyl containing peptide, (R,R)-1, had markedly higher affinity and agonist efficacy than its (S,S)-counterpart. Furthermore, the sulfo-Cy5 labeled (R,R)-14 retained high agonist potency as a novel fluorescent ligand for imaging Y4 receptors.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
Mengjie
M
Liu
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
Simon J
SJ
Mountford
School of Life Sciences, University of Nottingham , Queen's Medical Centre. Derby Road, Nottingham NG7 2UH, United Kingdom.
Rachel R
RR
Richardson
School of Life Sciences, University of Nottingham , Queen's Medical Centre. Derby Road, Nottingham NG7 2UH, United Kingdom.
Marleen
M
Groenen
School of Life Sciences, University of Nottingham , Queen's Medical Centre. Derby Road, Nottingham NG7 2UH, United Kingdom.
Nicholas D
ND
Holliday
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
Philip E
PE
Thompson
D000475:Alkenes / Q000737:chemistry* / Q000494:pharmacology*; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000494:pharmacology*; D002232:Carbocyanines / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D061848:Optical Imaging; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017476:Receptors, Neuropeptide Y / Q000819:agonists* / Q000032:analysis / Q000378:metabolism
D000475:Alkenes; D019440:Anti-Obesity Agents; D002232:Carbocyanines; D010455:Peptides; D017476:Receptors, Neuropeptide Y; C085321:cyanine dye 5; C109491:neuropeptide Y4 receptor