2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-PHEN) has been previously synthesized to obtain a potential prodrug capable of release Dopamine (DA) into CNS. However, DA-PHEN could act per se as a dopaminergic drug. In this study, the permeability transport (Pe), obtained by parallel artificial permeability assay (PAMPA), indicated a low passive transcellular transport (Pe=0.32  0.01•10-6 cm/s). Using the Caco2 cell system, the Papp-AP-BL in absorptive direction (3.36 ± 0.02•10-5 cm/s) was significantly higher than the Papp BL-AP in secretive direction (1.75 ± 0.07•10-5 cm/s), suggesting a polarized transport. The efflux ratio (Papp-AP-BL/Papp BL-AP=0.52 ± 0.02) indicated a low affinity of DA-PHEN to efflux carriers. The Forced Swim Test highlighted a reduction of immobility time in both Pretest and Test sessions (p<0.0001), with an exacerbation in the number of Headshakes and Divings in the Pretest (p<0.0001). Morris Water Maze strengthened the hypothesis that DA-PHEN induces adaptive responses to environmental challenges which are involved on cognitive functions (DA-PHEN vs CTR: escape latency; p<0.001; distance swum p<0.001, time spent on target quadrant p<0.001), without any change in locomotor activity for the administered dose. The molecular docking revealed the interaction of DA-PHEN with the identified D1 site mapping human brain receptor.

De Caro, V., Sutera, F.M., Gentile, C., Tutone, M., Livrea, M.A., Almerico, A.M., et al. (2015). Studies on a new potential dopaminergic agent: in vitro BBB permeability, in vivo behavioural effects and molecular docking evaluation. JOURNAL OF DRUG TARGETING, 23(10), 910-925 [10.3109/1061186X.2015.1035275].

Studies on a new potential dopaminergic agent: in vitro BBB permeability, in vivo behavioural effects and molecular docking evaluation

DE CARO, Viviana
;
SUTERA, Flavia Maria;GENTILE, Carla;TUTONE, Marco;LIVREA, Maria Antonia;ALMERICO, Anna Maria;CANNIZZARO, Carla;GIANNOLA, Libero Italo
2015

Abstract

2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-PHEN) has been previously synthesized to obtain a potential prodrug capable of release Dopamine (DA) into CNS. However, DA-PHEN could act per se as a dopaminergic drug. In this study, the permeability transport (Pe), obtained by parallel artificial permeability assay (PAMPA), indicated a low passive transcellular transport (Pe=0.32  0.01•10-6 cm/s). Using the Caco2 cell system, the Papp-AP-BL in absorptive direction (3.36 ± 0.02•10-5 cm/s) was significantly higher than the Papp BL-AP in secretive direction (1.75 ± 0.07•10-5 cm/s), suggesting a polarized transport. The efflux ratio (Papp-AP-BL/Papp BL-AP=0.52 ± 0.02) indicated a low affinity of DA-PHEN to efflux carriers. The Forced Swim Test highlighted a reduction of immobility time in both Pretest and Test sessions (p<0.0001), with an exacerbation in the number of Headshakes and Divings in the Pretest (p<0.0001). Morris Water Maze strengthened the hypothesis that DA-PHEN induces adaptive responses to environmental challenges which are involved on cognitive functions (DA-PHEN vs CTR: escape latency; p<0.001; distance swum p<0.001, time spent on target quadrant p<0.001), without any change in locomotor activity for the administered dose. The molecular docking revealed the interaction of DA-PHEN with the identified D1 site mapping human brain receptor.
Settore CHIM/09 - Farmaceutico Tecnologico Applicativo
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/10 - Biochimica
Settore BIO/14 - Farmacologia
De Caro, V., Sutera, F.M., Gentile, C., Tutone, M., Livrea, M.A., Almerico, A.M., et al. (2015). Studies on a new potential dopaminergic agent: in vitro BBB permeability, in vivo behavioural effects and molecular docking evaluation. JOURNAL OF DRUG TARGETING, 23(10), 910-925 [10.3109/1061186X.2015.1035275].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/131492
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