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

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 (P-e), obtained by parallel artificial permeability assay (PAMPA), indicated a low passive transcellular transport (P-e = 0.32 +/- 0.01 x 10(-6) cm/s). Using the Caco-2 cell system, the P-app (AP-BL) in absorptive direction (3.36 +/- 0.02 x 10(-5) cm/s) was significantly higher than the Papp BL-AP in secretive direction (1.75 +/- 0.07 x 10(-5) cm/s), suggesting a polarized transport. The efflux ratio (P-app (AP-BL)/P-app (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.