2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands

Authors
Párraga, Javier; Cabedo, Nuria; Andújar, Sebastián Antonio; Piqueras, Laura; Moreno, Laura; Galán, Abraham; Angelina, Emilio Luis; Enriz, Ricardo Daniel; Ivorra, María Dolores; Sanz, María Jesús; Cortes, Diego
Publication Year
2013
Language
English
Format
article
Status
Published version
Description
Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure–activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation.
Fil: Párraga, Javier. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Cabedo, Nuria. Universidad Politécnica de Valencia. Centro de Ecología Química Agrícola e Instituto Agroforestal Mediterráneo; España
Fil: Andújar, Sebastián Antonio. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Piqueras, Laura. Universidad de Valencia. Facultad de Medicina. Departamento de Farmacología; España
Fil: Moreno, Laura. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Galán, Abraham. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Angelina, Emilio Luis. Universidad Nacional de San Luis; Argentina
Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Ivorra, María Dolores. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Fil: Sanz, María Jesús. Universidad de Valencia. Facultad de Medicina. Departamento de Farmacología; España. Instituto de Investigación Sanitaria; España
Fil: Cortes, Diego. Universidad de Valencia. Facultad de Farmacia. Departamento de Farmacología, Laboratorio de Farmacoquímica; España
Subject
Tetrahydroprotoberberines
Dopamine receptors
Structureeactivity relationships cytotoxicity
Theoretical calculations
Bioquímica y Biología Molecular
Ciencias Biológicas
CIENCIAS NATURALES Y EXACTAS
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/4361