Rose Bengal analogs and vesicular glutamate transporters (VGLUTs).
Vesicular glutamate transporters (VGLUTs) allow the loading of presynaptic glutamate vesicles and thus play a critical role in glutamatergic synaptic transmission. Rose Bengal (RB) is the most potent known VGLUT inhibitor (Ki 25 nM); therefore we designed, synthesized and tested in brain preparations, a series of analogs based on this scaffold. We showed that among the two tautomers of RB, the carboxylic and not the lactonic form is active against VGLUTs and generated a pharmacophore model to determine the minimal structure requirements. We also tested RB specificity in other neurotransmitter uptake systems. RB proved to potently inhibit VMAT (Ki 64 nM) but weakly VACHT (Ki>9.7 microM) and may be a useful tool in glutamate/acetylcholine co-transmission studies.
Pietrancosta
Nicolas
N
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601 CNRS, Université Paris Descartes, 45 rue des Saints-Pères, 75270 Paris 06, France.
Kessler
Albane
A
Favre-Besse
Franck-Cyril
FC
Triballeau
Nicolas
N
Quentin
Thomas
T
Giros
Bruno
B
El Mestikawy
Salah
S
Acher
Francine C
FC
D000818:Animals; D008956:Models, Chemical; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D012395:Rose Bengal / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D050496:Vesicular Glutamate Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D050496:Vesicular Glutamate Transport Proteins; D012395:Rose Bengal