Novel codrugs with GABAergic activity for dopamine delivery in the brain
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- 作者：Nunzio Denora ; Tommaso Cassano ; Valentino Laquintana ; Antonio Lopalco ; Adriana Trapani ; Concetta Stefania Cimmino ; Leonardo Laconca ; Andrea Giuffrida ; Giuseppe Trapani
- 关键词：ANOVA ; analysis of variance ; BBB ; blood&ndash ; brain barrier ; BBMECs ; bovine brain microvessel endothelial cells ; CBR ; central benzodiazepine Receptor ; CDI ; 1 ; 1&prime ; -carbonyldiimidazole ; CNS ; central nervous system ; DA ; dopamine ; DMSO ; dimethylsulfoxide
- 刊名：International Journal of Pharmaceutics
- 出版年：2012
- 出版时间：1 November, 2012
- 年：2012
- 卷：437
- 期：1-2
- 页码：221-231
- 全文大小：610 K
文摘
This study investigates the use of codrugs of the GABAergic agent 2-phenyl-imidazo[1,2-a]pyridinacetamide and dopamine (DA) or ethyl ester L-Dopa (LD) as a strategy to deliver DA and simultaneously activate GABA-receptors in the brain. For this purpose, both DA and LD ethyl ester were linked by carbamate bond to imidazo[1,2-a]pyridine acetamide moieties to yield two DA- and two LD-imidazopyridine derivatives. These compounds were evaluated in vitro to assess their stability, binding affinities and cell membrane transport, and in vivo to assess their bio-availability via microdialysis studies. The two DA derivatives were adequately stable in buffered solution, but underwent cleavage in diluted human serum. By contrast, the LD derivatives were unstable in buffered solution. Receptor binding studies showed that the DA-imidazopyridine carbamates had binding affinity for benzodiazepine receptors in the nanomolar range. Brain microdialysis experiments indicated that intraperitoneal administration of the DA derivatives sustained DA levels in rat striatum over a 4-h period.
These results suggest that DA-imidazopyridine carbamates are new DA codrugs with potential application for DA replacement therapy.