Studies on a new potential dopaminergic agent: in vitro BBB permeability, in vivo behavioural effects and molecular docking evaluation
| Autor: | Carla Gentile, M. A. Livrea, Marco Tutone, Anna Maria Almerico, Viviana De Caro, Libero Italo Giannola, Flavia Maria Sutera, Carla Cannizzaro |
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| Přispěvatelé: | De Caro, V, Sutera, FM, Gentile, C, Tutone, M, Livrea, MA, Almerico, AM, Cannizzaro, C, Giannola, LI |
| Rok vydání: | 2015 |
| Předmět: |
Dopamine
Phenylalanine Dopamine Agents Pharmaceutical Science Morris water navigation task Pharmacology Biology Cognitive flexibility Permeability In vivo Settore BIO/10 - Biochimica PAMPA-BBB medicine Humans In vivo behavioural effect Dopaminergic Prodrug Settore CHIM/08 - Chimica Farmaceutica Molecular Docking Simulation Settore CHIM/09 - Farmaceutico Tecnologico Applicativo Blood-Brain Barrier Paracellular transport Molecular docking D1-receptor Settore BIO/14 - Farmacologia Efflux Caco-2 bidirectional assay Caco-2 Cells Transcytosis Behavioural despair test medicine.drug |
| Zdroj: | Journal of drug targeting. 23(10) |
| ISSN: | 1029-2330 |
| Popis: | 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 Caco-2 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 pre-test 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 versus 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. |
| Databáze: | OpenAIRE |
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