TY - JOUR
T1 - Novel codrugs with GABAergic activity for dopamine delivery in the brain
AU - Denora, Nunzio
AU - Cassano, Tommaso
AU - Laquintana, Valentino
AU - Lopalco, Antonio
AU - Trapani, Adriana
AU - Cimmino, Concetta Stefania
AU - Laconca, Leonardo
AU - Giuffrida, Andrea
AU - Trapani, Giuseppe
N1 - Funding Information:
This work was supported by a grant from Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MIUR) and from NS050401 (to AG). We thank Dr. M. De Candia (Department of Pharmacy, University of Bari) for his help with the Exp log P measurements and Mr Giovanni Dipinto and Mr Antonio Palermo for their skilful technical assistance in recording mass spectra and NMR spectra, respectively.
Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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.
AB - 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.
KW - Blood-brain barrier
KW - Codrugs
KW - Drug targeting
KW - MDCKII-MDR1 cell
KW - Microdialysis
KW - P-glycoprotein
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U2 - 10.1016/j.ijpharm.2012.08.023
DO - 10.1016/j.ijpharm.2012.08.023
M3 - Article
C2 - 22940209
AN - SCOPUS:84866743619
VL - 437
SP - 221
EP - 231
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
IS - 1-2
ER -