Synthesis, dopaminergic profile, and molecular dynamics calculations of N-aralkyl substituted 2-aminoindans

SEBASTIAN A. ANDUJAR, BIAGINA MIGLIORE DE ANGEL, JAIME E. CHARRIS, ANITA ISRAEL, HEBERTO SUAREZ-ROCA, SIMON E. LOPEZ, MARIA R. GARRIDO, ELVIA VICTORIA CABRERA, GONZALO VISBAL, CECIRE ROSALES, FERNANDO D. SUVIRE, RICARDO D. ENRIZA, AND JORGE E. ANGEL-GUIO

BIOORGANIC & MEDICINAL CHEMISTRY.

Año: 2008 p. 3233 - 3244

0968-0896

Brain dopaminergic system has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson’sdisease, depression, and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems areattributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effectsrepresents 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 compoundwas assayed as a diastereoisomeric mixture in two experimental models: stereotyped behavior (gnaw) and renal urinaryresponse, 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 inhibitoryeffect 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 mixturefor 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 understandthe experimental results we performed molecular dynamics simulations of two complexes: compound 3/D2DAR (dopaminereceptor) and compound 4/D2DAR. The differential binding mode obtained for these complexes could explain the antagonistand agonist activity obtained for compounds 3 and 4, respectively. 2007 Elsevier Ltd. All rights reserved.