Inhibition of vesicular glutamate uptake by Rose Bengal-related compounds: structure-activity relationship.
Synaptic vesicular accumulation of glutamate is a vital initial step in glutamate transmission. We have previously shown that Rose Bengal, a polyhalogenated fluorescein analog, is a potent inhibitor of glutamate uptake into synaptic vesicles. Here, we report the structural features of Rose Bengal required for this inhibition. Various Rose Bengal-related compounds, with systematic structural variations, were tested. Results indicate that the four iodo groups and the phenyl group attached to the xanthene moiety are critical for potent inhibitory activity. Replacement of these groups with two iodo groups and an alkyl group, respectively, results in substantial reduction in potency. Of further interest in creating high potency is the critical nature of the oxygen atom which links the two benzene rings of xanthene. Thus, the phenyl group and multiple iodo groups, as well as the bridging oxygen of xanthene, are crucial elements of Rose Bengal required for its potent inhibitory action.
Bole
David G
DG
Mental Health Research Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109-0669, USA.
Ueda
Tetsufumi
T
D000818:Animals; D010697:Eosine I Bluish; D004923:Erythrosine / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology; D066298:In Vitro Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012395:Rose Bengal / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D012395:Rose Bengal; D018698:Glutamic Acid; D010697:Eosine I Bluish; D004923:Erythrosine