Artículo
Synthesis, dopaminergic profile, and molecular dynamics calculations of N-aralkyl substituted 2-aminoindans
Andujar, Sebastian Antonio
; de Angel, Biagina Migliore; Charris, Jaime E.; Israel, Anita; Suárez Roca, Heberto; López, Simon E.; Garrido, Maria R.; Cabrera, Elvia Victoria; Visbal, Gonzalo; Rosales, Cecire; Suvire, Fernando Daniel; Enriz, Ricardo Daniel
; Angel Guío, Jorge E.
Fecha de publicación:
03/2008
Editorial:
Pergamon-Elsevier Science Ltd
Revista:
Bioorganic & Medicinal Chemistry
ISSN:
0968-0896
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Brain dopaminergic system has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression, and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to synthesize N-[2-(4,5-dihydroxyphenyl)-methyl-ethyl]-4,5-dihydroxy-2-aminoindan hydrobromide (3), planned to be a dopamine ligand, and to evaluate its dopaminergic action profile. This compound was assayed as a diastereoisomeric mixture in two experimental models: stereotyped behavior (gnaw) and renal urinary response, after central administration. The pharmacological results showed that compound 3 significantly blocked the apomorphine-induced stereotypy and dopamine-induced diuresis and natriuresis in rats. Thus, compound 3 demonstrated an inhibitory effect on dopaminergic-induced behavior and renal action. N-[2-(-Methyl-ethyl)]-4,5-dihydroxy-2-aminoindan hydrobromide (4) was previously reported as an inotropic agent, and in the present work it was also re-evaluated as a diastereoisomeric mixture for its possible central action on the behavior parameters such as stereotypy and dopamine-induced diuresis and natriuresis in rats. Our results indicate that compound 4 produces an agonistic response, possibly through dopaminergic mechanisms. To better understand the experimental results we performed molecular dynamics simulations of two complexes: compound 3/D2DAR (dopamine receptor) and compound 4/D2DAR. The differential binding mode obtained for these complexes could explain the antagonist and agonist activity obtained for compounds 3 and 4, respectively.
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Articulos(IMIBIO-SL)
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Citación
Andujar, Sebastian Antonio; de Angel, Biagina Migliore; Charris, Jaime E.; Israel, Anita; Suárez Roca, Heberto; et al.; Synthesis, dopaminergic profile, and molecular dynamics calculations of N-aralkyl substituted 2-aminoindans; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 16; 6; 3-2008; 3233-3244
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