title: Studies on a new potential dopaminergic agent: in vitro BBB permeability, in vivo behavioural effects and molecular docking evaluation.
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 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.
authors.affiliation: a Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF) , Università degli Studi di Palermo , Palermo , Italy .
authors.forename: Viviana
authors.initials: V
authors.lastname: De Caro
authors.affiliation: b Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BioNeC) , Università degli Studi di Palermo , Palermo , Italy , and.
authors.forename: Flavia Maria
authors.initials: FM
authors.lastname: Sutera
authors.affiliation: a Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF) , Università degli Studi di Palermo , Palermo , Italy .
authors.forename: Carla
authors.initials: C
authors.lastname: Gentile
authors.affiliation: a Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF) , Università degli Studi di Palermo , Palermo , Italy .
authors.forename: Marco
authors.initials: M
authors.lastname: Tutone
authors.affiliation: a Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF) , Università degli Studi di Palermo , Palermo , Italy .
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Livrea
authors.affiliation: a Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF) , Università degli Studi di Palermo , Palermo , Italy .
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Almerico
authors.affiliation: c Dipartimento di Scienze per la Promozione della Salute e Materno Infantile "G. D'Alessandro" , Università degli Studi di Palermo , Palermo , Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Cannizzaro
authors.affiliation: a Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF) , Università degli Studi di Palermo , Palermo , Italy .
authors.forename: Libero Italo
authors.initials: LI
authors.lastname: Giannola
mesh_terms: D001812:Blood-Brain Barrier / Q000187:drug effects*; D018938:Caco-2 Cells; D004298:Dopamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015259:Dopamine Agents / Q000493:pharmacokinetics*; D006801:Humans; D062105:Molecular Docking Simulation; D010539:Permeability; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D057900:Transcytosis
chemical_list: C553723:2-amino-N-(2-(3,4-dihydroxyphenyl)ethyl)-3-phenylpropionamide; D015259:Dopamine Agents; D010649:Phenylalanine; D004298:Dopamine
keywords: Caco-2 bidirectional assay; PAMPA-BBB; cognitive flexibility; in vivo behavioural effects; molecular docking D1-receptor