Design, synthesis and preliminary evaluation of dopamine-amino acid conjugates as potential D1 dopaminergic modulators.
The dopamine-amino acid conjugate DA-Phen was firstly designed to obtain a useful prodrug for the therapy of Parkinson's disease, but experimental evidence shows that it effectively interacts with D1dopamine receptors (D1DRs), leading to an enhancement in cognitive flexibility and to the development of adaptive strategies in aversive mazes, together with a decrease in despair-like behavior. In this paper, homology modelling, molecular dynamics, and site mapping of D1 receptor were carried out with the aim of further performing docking studies on other dopamine conjugates compared with D1 agonists, in the attempt to identify new compounds with potential dopaminergic activity. Two new conjugates (DA-Trp 2C, and DA-Leu 3C) have been identified as the most promising candidates, and consequently synthesized. Preliminary evaluation in terms of distribution coefficient (DpH7.4), stability in rat brain homogenate, and in human plasma confirmed that DA-Trp (2C), and DA-Leu (3C) could be considered as very valuable candidates for further in vivo studies as new dopaminergic drugs.
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Via Archirafi 32, 90123, Palermo, Italy. Electronic address: marco.tutone@unipa.it.
Marco
M
Tutone
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Via Archirafi 32, 90123, Palermo, Italy; Humanitas Clinical and Research Center, Via Manzoni 113, 20089, Rozzano, MI, Italy.
Aurora
A
Chinnici
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Via Archirafi 32, 90123, Palermo, Italy.
Anna Maria
AM
Almerico
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Via Archirafi 32, 90123, Palermo, Italy.
Ugo
U
Perricone
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Via Archirafi 32, 90123, Palermo, Italy; SiSaf Ltd, Innovation Centre, Northern Ireland Science Park, Queen's Island, Belfast, BT3 9DT, UK.
Flavia Maria
FM
Sutera
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Via Archirafi 32, 90123, Palermo, Italy.
Viviana
V
De Caro
D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000378:metabolism; D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D004298:Dopamine / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015259:Dopamine Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D062105:Molecular Docking Simulation; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000737:chemistry / Q000378:metabolism*
D000596:Amino Acids; D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D004298:Dopamine
Amino acids; Conjugates; Docking; Dopamine; Molecular modelling; PCA; Synthesis